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CHEMICAL CONSTITUTION 


AND 


PHYSIOLOGICAL ACTION 


BY 


Pror. Dr. LEOPOLD SPIEGEL 


(BERLIN) y' 


TRANSLATED WITH ADDITIONS 
FROM THH GERMAN 


BY 
C. LUEDEKING ann A. C. BOYLSTON 


(PH.D., LEIPSIC) (A.M., HARVARD 





~NEW YORK 
D. VAN NOSTRAND COMPANY 
25 PARK PLACE 
| 1915 


CopYRIGHT, 1915 
BY 
D. VAN NOSTRAND COMPANY 


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THE SCIENTIFIC PRESS 
ROBERT DRUMMOND AND COMPANY 
BROOKLYN, N. Y. 


FOREWORD 


THE action of chemical agents upon the animal organ- 
ism, and particularly upon man, is of the greatest 
importance and interest. Far too little has been done 
toward systematizing our knowledge of this subject, 
and there is no doubt that this field offers an enormous 
opportunity for useful research. 

The purpose and scope of the present treatise have 
seemed sufficiently distinct from other works, and of 
sufficient importance to justify its translation. We have 
also attempted to bring the work up to date by a con- 
sideration of some of the more recent literature. 

The borderlands between the formerly distinct sciences 
are becoming of more and more importance as each 
science progresses. The relation between chemical con- 
stitution and physiological action is of such fundamental. 
and far-reaching significance that a general.idea of the 
work which has already been done should be of interest 
not only to the physiological chemist and to the searcher 
for new synthetic therapeutic agents, but also to the 
physician who must prescribe the use of such com- 
pounds. For real, rational scientific medicine must be 
founded upon a knowledge of this subject, and in order 
that a steady progress shall be made, a systematic 
knowledge must replace haphazard and empirical in- 
formation. : 


ill 


3464<0 


iv FOREWORD 


This work is presented with the hope that it may 
aid not only in the search for new synthetic therapeutic 
agents, but also in a more thorough understanding of the 
action dnd the reasons for the action of many of the com- 
pounds which are already in use. 


CONTENTS 


PAGE 

BORE WOME as vw is eae ash ea ae Pe ee iil 
CBNEBAL, CORBIDERATIONG » . 6... ss lv Rsibs 8b OR eR oe vee me 1 
RRORGANIC: CMPD CMON oo iors sv bec des ee aan BOE Dek 24 
SIRGANIO SN OMPOTIIINS ees cds sho ale den cies eb a eemes 43 
(ene ates oe os a ook hn oe dee a ee 43 
Aldetiydes and Ketones. 2. i! 4 his ev eee a 50 

ACIGS ROG: LIVER i Ob oS eek en 8G Se Cees 54 

(b) Aromatic Series .......0.5....... See te PRR ieee Pe ents 63 
Hydroaromatic Compounds. ............ccececcccs 72 

tuner Disinieotion | kas sok cee cee eee es 77 

(¢) Nitrogen Compounds 62°00 ea 8 a es oe 80 
Ammonia and Simpler Derivatives................. 80 
Ammonia Baaee. 60 i ee ele es ie a 96 

Cyclic Bases and Alkaloids ic. 3 Cc ee ee as 100 
Atropine—Cocaine Group......... 0.0. ec eee ee cence 103 

Opium Alkaloids and Relatives............... HIP 118 

Veronal Grotip 3. vcs ses eee ae 128 

Quinine and Relatives........... Vea Cee oem s Mikes BOG 

PUTING CAPPED ois OOo oe Cok oe ee een Seen 144 
Hydrazine and Hydroxylamine.................... 149 
Hyponitrous Acid Derivatives. .................06. 151 


PROBE Ca es Mk Ec eae Ves cet. Perron eer? bern 152 


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CHEMICAL CONSTITUTION AND PHYSIO- 
LOGICAL ACTION 


GENERAL CONSIDERATIONS 


Descriptive chemistry has brought forth an enormous 
number of chemical compounds, and has showed us 
their properties. ‘The similarity of certain compounds 
which could be brought into genetic relationship, if not 
actually converted one to another, made possible the 
grouping of such bodies into series. This led to a 
classification of the chemical elements which directly 
explained reactions common to all the members of a 
series. General discrepancies which were observed were 
explained by assuming not only different valences for 
the different elements in combination, but also a vary- 
ing valence for a single element. Finally, the analogies 
between these series of elements were found to be related 
to the weight of the hypothetical atoms, and this re- 
sulted in the development of hypotheses connecting 
atomic weights with chemical and physical properties. 
The most perfect expression of such relations to-day is 
the periodic system of the elements. There were only 
timid attempts in the field of inorganic chemistry to 
explain the properties of compounds by discovering not 
only the kind and number of atoms in a combination, 
but also the manner in which they were joined—the 


2 <.).)\°. GENERAL CONSIDERATIONS 


constitution of the compounds. The most powerful 
impulse to this work came from the knowledge of the 
carbon compounds. For in these bodies a few elements 
form countless compounds’ whose properties range from 
those of a harmless brilliant dye to thosé of an apparently 
insignificant but really powerful poison alkaloid. In 
such a chaotic labyrinth it was impossible to find a path 
without the Ariadne thread of constitutional interpre- 
tation. : 

Organic chemists were therefore first in this work, 
systematically propounding and elaborating hypotheses, 
which were later applied to inorganic compounds. _ 

Real scientific chemistry begins, at least in the organic 
field, with the determination of the influence of consti- 
tution upon the various properties of the compounds. 

The primary object of investigation is to ascertain 
the effect of the inner structure upon chemical and phys- 
ical phenomena such as chemical reactivity, melting- 
point, boiling-point, heat of combustion, refractivity, 
dielectric constant, etc. 

Especial interest was early excited by the color of 
substances and particularly the property of imparting the 
original or a modified color to animal and plant fibers. 

Only in recent times has it been attempted to connect 
the chemical constitution of compounds with those 
properties which are most delicate and most important 
to man—that is, with their effect upon the animal 
organism. : 

Of course the idea of finding a connective relation 
between chemical and physiological properties of com- 
pounds is by no means new. This thought naturally 
arose with the earliest chemical considerations which 
were directed to substances of especial importance and 
interest to man, whether their qualities were injurious 


GENERAL CONSIDERATIONS 3 


or remedial. Then appeared the genius of Paracelsus, 
who directed chemistry into new courses with the sig- 
nificant expression, ‘‘ The real object of chemistry is 
not to make gold, but to prepare medicines.’ (Von 
Meyer, History of Chemistry, 2d ed. from 2d German 
ed.) 

He announced a proposition that has a decided smack 
of modern times when he said “The healthy human 


body is a combination of chemical substances; when 
this suffers any change, diseases arise, which: accordingly 
can be cured only by chemical remedies.” 

The further advancement we owe next.to the Iatro- 
chemical school, which proceeded along the course which 
Paracelsus had laid. This school, under de la Boé Sylvius, 
attempted to make all the science of medicine applied 
chemistry. .The pity is that in this development there 
sprang up beside really far-reaching and fundamental 
ideas the most vague and speculative phantasies and 
imaginings, which could not fail to discredit the whole 
science of chemistry for some time, particularly so in 
investigating the curative effects of compounds. 

Chemical and physiological knowledge was in too 
undeveloped a condition for us to expect a great deal 
of productive work from those times. In order that 
we may evaluate the effect produced upon life functions 
by the substances artificially ingested into the organism 
it is quite necessary, according to our present ideas, 
that we postulate that these substances enter into reac- 
tion with the constituents of the cells which transmit 
the effect to the whole organism. Then it becomes at 
once evident to the chemist that such an Interaction 
depends not only upon the structure of the ingested 
reagent, but quite as much upon the structure of the 
cell substances. 


oF GENERAL CONSIDERATIONS 


Thus we arrive at the discouraging conclusion that 
for a full and complete solution of our problems, for 
a sure and definite knowledge of the action of foodstuffs, 
medicines or poisons, it is quite certainly essential that 
we know the constitution of the cell substance and the 
significance of this constitution in the various physio- 
logical functions. Until this is known we must remain 
in the dark. At all events to-day, when the chemical 
constitution of one of the interacting materials—that 
is, the ingested substance, is known with a probability 
that borders upon certainty, we are facing our problem 
with views quite different from those which were cur- 
rent in the days of Paracelsus, Van Helmont and Sylvius. 
We may even allow ourselves to hope that these very 
relationships to whose investigation we are here devoted 
may become a means of assured progress in the deter- 
mination of the ultimate nature of the cell substances 
themselves. For the behavior of a substance toward 
known reagents gives us quite generally a clue to the 
presence of groups whose reaction characteristics we 
know. | 
At any rate if we were to limit ourselves even 
to-day to our investigation of the actions and effects 
of only those substances whose constitution may be 
considered to be wholly and perfectly cleared up in all 
details, our field would be comparatively small. For 
we must remember that it is in a series of substances 
whose constitution has so far defied all attempts at 
solution where we find some of the physiologically most 
active material. But there are fortunately many per- 
tinent relationships that can be established even with 
our very limited knowledge of constitutional structure, 
just as is the case in pure chemistry. For example, 
it is not at all necessary to know the structure of aro- 


GENERAL CONSIDERATIONS 5 


matic hydrocarbons in order to conclude definitely after 
noting the varying behavior of their nitro derivatives 
on the one hand, and the corresponding amines formed 
by reduction of these nitro bodies on the other hand, as 
compared with the corresponding diazonium salts, that 
the amino group on the aromatic nucleus plays an 
important and especial role in the reactions involved. 
In the same manner in the case of physiologically active 
substances we can easily trace the influence of various 
substitutions, although the actual constitution and 
occasionally even the empirical composition of <the main 
body of the compound may be entirely unknown to us. 
In the cases of some substances the living organism is 
an indicator of such remarkably great delicacy that it 
far transcends all chemical reagents and reminds us 
strongly of the sensitiveness of the electroscope in the 
detection of radioactive substances. For example, the 
living organism demonstrates most clearly changes of 
this sort in the formation of specific anti-bodies from 
the normal components of the animal body. Such 
changes could not even be surmised by any chemical 
reagents, although there can be no. question that for 
their fundamental causes they must be referred to alter- 
ation of the chemical and stearic structure of complex 
molecules. — 

As we have already noted, material ingested from 
without enters into relationship with the body materials 
in the performance of the various body functions. In 
general the more these ingested substances differ from 
those of the body and the greater the effect observed 
by the introduction of the most minute quantities, so 
much the more easily may these relationships be deter- 
mined. Both of these conditions are well satisfied in 
the case of those substances which are in part injurious 


6 GENERAL CONSIDERATIONS 


to the body as poisons and in part beneficial as med- 
icines. We shall therefore essentially restrict ourselves 
to a consideration of these substances in the following 
treatise. : 

First of all let us consider what quantities of foreign 


substance introduced into the body are capable of being _ 


recognized by a definite effect. Hydrocyanic acid is 
fatal for man in doses of 0.05 gm., and its effects are 
very clearly discernible in doses of 0.0005 gm. Strych- 
nine, which is fatal for adult man in doses of 0.10 gm. 
to 0.12 gm., shows a very marked effect even in doses 
of 0.003 gm. Pilocarpine is utilized in a therapeutic 
way for man in quantities of 0.005 gm. Let us for a 
moment consider these small quantities to be distributed 
only in the blood, which in an adult human being is 
estimated at 5.5 kgm. We then find the following 
concentrations in the blood for doses that are effective: 


Hydrocyanic acid.......... 1 : 11,000,000 
SIFVENNING.. Poe as oes 1: 1,800,000 
PHUOCAIPING. 25 oc, se Sere a) 1,300,080 


Now for some of the particularly delicate chemical 
reactions the following limits of sensitiveness have been 
found: 


AgNOsz and HOM 2... 5.06% 1: 1,000,000 
BaCle and HeSO4 sg SY ay ded whe Ls 400,000 


A further consideration of the above figures makes 
it seem improbable that the quantities of the poisons 
mentioned are so uniformly distributed in the organism 
as is assumed in the calculation. We are rather led to 
the view that a localization or concentration takes place 
at those parts that are affected, in somewhat the same 
manner as a woolen thread can concentrate and make 


GENERAL CONSIDERATIONS 7 


distinctly visible a very slight and uncertain color in 
a solution. And indeed it has been possible by intra- 
vital staining with proper dye-stuffs to furnish proof 
of such a localization within the organism. Thus, for 
example, methylene blue imparts a particularly intense 
color to the nerve endings, certain cells of the pancreas 
and a definite category of muscle fibers endowed with 
particular functions.t At the same time it has been 
possible by means of this same coloring-matter to estab- 
lish differences in chemical characteristics of the cells 
which absorb it. It is taken up inf part as a leuco base 
and in part is transformed into a compound which 
regenerates methylene blue only on treatment with 
hydrochloric acid. The power of coloring gray nerve 
matter is possessed by only a small number of dyes, 
especially basic dyes. All dyes that contain a sulphonic 
acid group are in this respect entirely ineffective and 
of the acid dyes containing hydroxyl as the auxochrome 
group alizarine alone is effective. : ) 
Phenomena of this sort, at first noted only as interesting 
facts, were utilized later, particularly by Ehrlich, as 
a basic starting point for a comprehensive tracing out 
of physiological action. We must tarry for a moment 
while on this interesting point. The first question which 
naturally arises is how we can recognize a localization 
when we are dealing with substances other than those 
we have just discussed—that is, with substances whose 
presence cannot be plainly detected by the eye, as 
is the case with coloring matters. When we have under 
consideration the living being, then, of course the hypoth- 
esis that such localization is the cause of the general 
physiological effect, helps us out of our difficulty. By 


1 Ehrlich, Leyden-Festschrift, Vol. I. 
2 Herter, Z. physiol. Chem., 42, 493 (1904). 


¥ 


8 GENERAL CONSIDERATIONS 


careful study of the physiological effects we can deter- 
mine when ‘the ingested foreign substance has become 
localized if we know the seat of the function that has 
been affected. ‘Thus we may learn the organ upon which 
this function is dependent and so the brain centers 
and nerve fibers concerned in the effect. For all such 
information as this we are of course indebted to the 
present state of development of anatomy and phys- 
iology. Naturally we must determine by experiment 
in the individual case whether the influence is to be 
traced to the organ ‘itself or to the brain center that 
controls it, or whether the nerve fiber that connects 
the two has been affected. Further observations can 
be made in the post mortem examination of the affected 
individual. Some substances leave at the seat of their 
localization distinct evidences in the form of histological 
changes; for example, the ecgonine derivatives in the 
parenchyma of the liver (Ehrlich) and curare in the nerve 
fibers (Cavallié). The localization of other substances 
can be detected directly by staining or by the addition of a ~ 
proper reagent. Thus, for example, it is possible to trace 
the iron absorption from the intestines by the intestinal 
epithelial cells, the lymphatic glands, etc., by treating 
the organs under suitable conditions with ammonium 
sulphide or with potassium ferrocyanide. Thus, also 
it is possible to ascertain the distribution of aniline 
in the organism by means of 1-2-naphthoquinone-4- 
sulphonic acid.! The further development of physio-- 
logical and histological anatomical methods will very 
probably bring to light many other possibilities in this 
field. : 

We may add that the localization of the toxines, 
immuno bodies, etc., which are so exceedingly sensitive 

1 Ehrlich and Herter, Z.-physiol. Chem., 41;°379 (1904). 


GENERAL CONSIDERATIONS 9 


in their reaction, can quite frequently be directly demon- 
strated by means of solution of the corresponding anti- 
bodies. 
Now this selective power, which has already been 
determined for a great number of substances and which 
we can reasonably expect to exist for many others, 
may depend upon either physical or upon chemical 
causes. 

Ehrlich compares the power of resorption possessed by 
individual organs for certain substances to the shaking- 
out process for alkaloids from their aqueous solution by 
means of organic solvents, such as ether, benzol, ligroin, 
etc. If we bear in mind that the liquids circulating in 
the body (blood and lymph) are essentially aqueous in 
character, but that the organs of vital importance, 
such as blood corpuscles, brain and nerves, are dis- 
tinguished by a content of fatty or wax-like substances, 
such as lecithines and cholesterines, then many physi- 
ological effects suggest the comparison. Hans Meyer 4 
as well as Overton? have shown that at least in the 
case of the neutral narcotics we have to do with more 
than a mere comparison, as here the degree of action 
increases in the same ratio as the quotient: 


Solubility in fat : solubility in water. 


There had previously been recognized relationships 
between the fat content of the brain and the degree 
of narcosis® that led von Bibra and Harless to the 
assumption that the essential feature of narcosis is the 
extraction of fat substances from the brain. This view 

1Hans Meyer, Arch. exp. Path. Pharm., 42, 109 (1899) and 
46, 337 (1901). Baum, ibid., 42, 119 (1899). 

2 Studien iiber die Narkose, Jena, 1901. 

*Kochmann, Biochem. Zentr., 4, 689 (1906). 


10 GENERAL CONSIDERATIONS 


has more recently been supported by the experiments 
of Reicher.! Further, Hermann has shown that all 
narcotics of the fatty series can dissolve red blood cor- 
puscles, and has explained this phenomenon as an extrac- 
tion of their fat-like substances. At the same time he 
calls attention to the coincidence of this process with 
the presumptive occurrence of narcosis. Reicher, on 
the other hand, had pointed out that the narcotic power 
of a substance is inveresly proportional to its solubility 
in water. ce 

The theory of Overton and Hans Meyer may be summed 
up in the following theorems propounded by them: 

(1) All primarily indifferent substances that are sol- 
vents for fat and fat-like bodies must act as narcotics. 
upon living protoplasm cells if they can be absorbed 
by the cells. 

(2) The action must appear first and strongest in those 
cells in whose composition these fat-like substances pre- 
dominate and in which they are especially essential 
contributors to the cell-function—in the nerve cells, - 
therefore, before all others. 

(3) The relative power for action of such narcotics 
must be dependent on the one hand upon their mechan- 
ical affinity for fat-like substances and on the other 
hand their lack of affinity for the remaining cell sub- 
stances—that is, principally water. So we can say 
their power depends upon the degree of their partition 
between water and the fat-like substances. 

i: This theory is borne out and substantiated by the 

- finding of similar relationships in other than the fatty 

series; but we cannot say that solubility in fat alone 

is the cause of narcosis. For such a conclusion as — 

that would very apparently imply that the neutral 
1 Reicher, Z. klin. Med., 65, 235 (1908). 


GENERAL CONSIDERATIONS 11 


fats should be counted among the most powerful of 
narcotics. So we must conclude that aside from these 
factors of solubility there must be taken into account 
some chemical factors of no less importance. 

Kochmann with perfect justice raises the objection 
that if the theory of Meyer is entirely valid all nar- 
cotics that act on the central system would of neces- 
sity act upon the peripheral nerves, at least temporarily 
paralyzing them, because they are very decidedly rich 
in lipoids, even if not to such an extent as is the brain. 
But, according to Gradenwitz,! this is not the case. 

Now there are very definite observations that point 
to the presence of chemical action in narcosis. 

The objection may very properly be made to the theory 
of von Bibra and Harless that the rapid return to the 
normal state contradictsit. Thisis Kochmann’s argument. 

Neverthless the fact which they have established re- 
mains—that is, that the quantity of fat capable of 
being extracted (from the brain during narcosis) is 
less than the quantity that can normally be extracted. 
Therefore, if this fat has not been removed from the 
cells, it must have undergone a change through the 
. action of the narcotic. Moore and Roaf? have shown 
that chloroform and other anzsthetics combine with 
protoplasm to form unstable compounds, and _ they 
presume that the formation of such compounds is the 
cause of the intoxication. The possibility of the for- 
mation of such compounds by the union of substances 
supposedly incapable of chemical combination has been 
thoroughly discussed by Heymans and de Buck? 


1 Gradenwitz, Dissertation, Breslau, 1898. 
2 Moore and Roaf, Proc. Roy. Soc., 73, 494 (1904); and 77, 
86 (1906). ; 
~ 8 Heymans and de Buck, Arch. intern. pharmacodyn., 1, 1 (1894). 


12 GENERAL CONSIDERATIONS 


So Kochmann fairly propounds the question: does 
the solubility in the fat perhaps merely serve as a means 
to an end? It may be absolutely necessary only in order 
that the narcotic may enter the cell without being an 
etiological causative factor. In view of this discussion 
we must decide that the power to dissolve in fat is essen- 
tial as the chief cause for the entry of the narcotic into 
certain organs. Therefore this factor within a given 
group of substances related in action will determine the 
degree of their activity. 

A treatment similar to the one we have made concern- 
ing solubility may also be applied to osmotic pressure 
and to surface tension in order to explain physiological 
differences in action of various substances. Nothing 
could be more desirable than to subject to mathematical 
treatment the complicated situation which we have in 
the action of foreign substances in the organism. But 
as yet we should have to deal with too great a number 
of variables at one time, and until some of the rela- | 
tionships that are still almost unknown to us shall have 
been positively established, such a treatment can hardly 
be applied. A premature attempt of the sort, which 
frequently results in treating as negligible factors the 
clear deductions of physiological observations, can only 
lead to discredit of the mathematical method. 

Loew ! assumed a direct chemical union of the proto- 
plasm with the so-called substituting poisons, supposing 
the labile amino and aldehyde groups of the protoplasm 
to be active in effecting such a union. In such a case 
then, the poisonous substances to be considered must 
have certain groups whith are capable of reaction with 
these amino and aldehyde groups even in very dilute 


1Loew Ein natiirliches System der Giftwirkungen, Stuttgart 
(1893). 


GENERAL CONSIDERATIONS 13 


solutions. Such an explanation seems to be, at least 
in some instances, quite plausible. For example, hydrox- 
ylamine and the hydrazines, which are well-known alde- 
hyde reagents, are powerful poisons for vegetable and 
animal organisms, while the ketoximes, in which the 
reaction group is bound, are only in exceptional cases 
more poisonous than the related ketones. Moreover, 
aniline, which reacts with aldehyde with far greater 
difficulty than does phenylhydrazine, is also, as we should 
expect, far less poisonous. In the case of a few poison- 
ous bodies having a tertiary nitrogen, a reduction with 
the formation of an imino group and consequently 
greater chemical activity increases their poisonous effects. 
In this connection may be mentioned the reduction of 
pyridine to piperidine. It is quite presumable also that 
in this category should be placed those bases whose 
power for action may be diminished by the entry of 
alkyl groups. This is particularly the case when an 
acid radicle is introduced into an amino group. In 
other cases, however, this hypothesis fails and is not 
supported by the facts. Erhlich will not admit this 
hypothesis at all for ingested foreign poisons, because 
in his very numerous experiments in this direction he 
was never able to establish that there had been a chem- 
ical union of such bodies. In fact, he found that the 
various poisons could, without exception, be again ex- 
tracted from the tissues by means of neutral, chemically 
inactive solvents.- Further, he opposes the Loew theory 
with the following arguments. 

(1) The return from a condition of narcosis to the 
normal condition is rapid in the case. of most of the 
substances under consideration. 

(2) When dye-stuffs (such as fuchsine) which are 
capable of reacting with aldehyde to suffer a distinct 


14 GENERAL CONSIDERATIONS 


color change are used, there is no occurrence of such 
change. 

Ehrlich, however, assumes a real chemical union in 
the case of toxines of high molecular weight and in 
the case of substances such as food-stuffs which are 
capable of assimilation, and in such cases he maintains 
that the specific haptophoric groups of the substance 
combine with the receptors or side chains of the pro- 
toplasm. For foreign substances, he concludes as a 
result of his investigations, that there is such a union 


eat 
only in the case of dimethylenimine | PN and for 
CHy 
CH» 
the structurally analogous dimethylene oxide | O 
CHye 


because these substances effect a lasting and peculiar 
change in the tissue. 

Although we must acknowledge that the objections to 
the theory of Loew are in part justified, nevertheless, 
they themselves are not beyond criticism nor wholly 
free from fault. It is safe to presume that there are a 
number of substances that would show an action on the 
tissues similar to that of dimethylenimine. In fact, 
according to Ehrlich’s investigations, cocaine and most 
of the other ecgonine derivatives cause a characteristic 
foamy degeneration of the liver cells, and a more deli- 
cate microscopic technique has shown that cocaine and 
stovaine, which acts similarly, develop in the localities - 
of their action certain well-marked structural changes.! 
It will, therefore, without doubt, be necessary to widen 
the circle of exceptions to the Ehrlich law, and among 
these exceptions are most certainly to be included, 

1Santesson, Skand. Arch. Physiol., 21, 35; Chem. Zentr., 
1908, IT, 145. 


GENERAL CONSIDERATIONS 15 


according to Ehrlich’s own beautiful researches, the 
compounds or combinations of trivalent arsenic in their 
behavior toward trypanosomes.! 

The most weighty of the reasons adduced by Ehrlich 
in support of his contention is the fact that the poi- 
sonous substances can be removed from the tissues 
by means of neutral solvents. But even supposing a 
chemical union, this phenomenon can be explained by 
the law of mass action by assuming that the various 
protoplasm compounds are easily dissociated in the 
solvents. This would at the same time explain the 
evanescence of the narcosis. : 

In fact, we find in Overton’s work some results that 
indicate such a behavior. For example, if we place 
certain cells in a strychnine solution, there is formed 
within the cells a precipitate of strychnine tannate. 
This formation is proportionate to the concentration 
of the alkaloid in solution, and if this concentration is 
decreased by sufficiently diluting the solution, the pre- 
cipitate will disappear. Accordingly, a chemical union 
of the poisons would seem quite probable if their removal 
from the tissues proceeded only according to laws other 
than those that hold in the case of ordinary mixtures 
of substances.. And, in fact, this is supported by in- 
vestigations of Straub? who found that certain effects 
of alkaloids are dependent upon a preliminary storage 
in the sensitive cells. He also found that inactive 
alkaloids are either destroyed or are not stored up in the 
cells. Straub proved such a storage effect in the case 
of veratrine, and he further showed that here the par- 
tition coefficients differ from those demanded by the 
diffusion law. Denarcotization is also.effected by the 


1 Ehrlich, Ber., 42, 30 (1909). ; 
2 Straub, Pfliiger’s Arch., 98, 233 (1903). 


16 GENERAL CONSIDERATIONS 


blood and tissue fluids much more strongly than we 
should expect according to this law. Therefore, we 
must consider the fixation of the poison on the proto- 
plasm and its removal as a reversible reaction which 
may be represented by the following equation: 


Plasma+ poison solution= poison plasma-+water. 


Other instances of chemical fixation have already 
been mentioned in the discussion of the Overton-Meyer 
theory. 

' However this conflict of opinions as to the mechan- 
_ ism of the action may be decided, this at least is certain: 
_ The production of an effect at any desired place in the 
organism necessitates such a chemical constitution of 
_ the ingested substances as to make possible their local 
) fixation, whether it be of a chemical or of a physical 
_ nature. When there is such a structure of the material, 
- this acts, we may say, as a grappling hook by means of 
' which the effective groups can be attached or hooked 
on to the substance of the tissue.! 

It is necessary, of course, to avoid the previous accu- 
mulation in the protoplasm of such groups as have the 
same or a similar selective tendency as the substance 
we desire to bring into action.. Otherwise our efforts 
at directive medication would be fruitless. This dis- 
cussion clearly emphasizes the great practical value of — 
research upon the mode of action of the different sub- 
stituting groups and upon the group characteristics 
which enable them to react upon or become attached 
to the different body organs. It is also apparent that 
the synthesis of medicinal preparations depends upon 
the scientific advance of such considerations. 

1 Ehrlich, Leyden-Festschrift. 


GENERAL CONSIDERATIONS 17 


A research of this sort is conducted in two different 
ways. At first it was naturally directed to substances 
that had been determined in an empirical manner to be 
physiologically active. These were of course natural 
substances, principally plant products. The first object 
was to isolate from the raw product whether drug or 
coal tar, those chemical components which constituted 
the active principles. This course has been pursued 
for many decades since the isolation of morphine from 
opium, and is still being pursued to-day. Such activities 
have been remarkable for the energy which has been 
spent in them and for the resulting successes. Coin- 
cident with such work, particularly in later years, has 
been the work of unraveling the chemical constitution 
of the active principles obtained. Then followed the 
attempt to determine what particular parts of the mole- 
cule, what special groups, were responsible for the 
specific physiological action. For example, it is extremely 
interesting and valuable from a chemical standpoint to 
have the total synthesis of an alkaloid. But it is far 
more important from the standpoint of practical medi- 
cine to be able to modify such a body so as to deprive 
it of undesirable or unpleasant effects while still retaining 
its essential physiological properties or to increase or 
strengthen the desired effect, or lastly, to combine this 
with other desired effects which are lacking in the 
original substance. These efforts must be carried still 
further in order to make ourselves independent of the 
original substances of nature, and to make in their stead 
artificial substances, similar, but constituted as simply 
as possible. 

At the beginning of this work it was natural that it 
should be mainly directed toward the thoroughly known 
effects of substances traditionally offered us by nature. 


ae 


18 - GENERAL CONSIDERATIONS 


But soon the investigators were ready to leave this path 
to explore physiological effects with which the older 
observers were necessarily quite unacquainted. How 
much there may be that is physiologically not only 
interesting, but indeed valuable in the almost count- 
less numbers of compounds which the speculative inves- 
tigation and experimentation of the chemists have given 
us since Wohler’s synthesis of urea! Enormous as these 
possibilities are, they must continue to multiply to far 
greater numbers in the future. 

The second direction in which effort has turned for 
quite a period of time is the determination of the phys- 
iological behavior of many active chemical groups, 
some of them long known and some newly discovered. 
It is to be urgently desired from both a practical and 
a theoretical standpoint that this work will be con- 
ducted in a much more comprehensive and thorough 
way than hitherto. For, up to the present time, this — 
work has been usually done by pharmacologists either 
directly employed or supported by chemical factories, 
and it has been carried out merely with a view to its 
practical exploitation. Such work has had no real 
scientific aim and purpose. The theoretical develop- 
ment of the subject demands more thorough methods of 
investigation. The pursuit of vaguely suggested and 
often undesired effects can be successfully carried on 
only by the cooperation of the chemist and the phys- 
iologist. Thus only will the theoretical views on the 
influence of constitution be placed upon a secure and 
safe foundation. And it is almost self-evident that 
such investigation will be followed by an immense amount 
of information of practical value, at least in a general » 
understanding and conception of the subject. Such 
investigations are of sufficient importance for the wel- 


GENERAL CONSIDERATIONS 19 


fare of mankind to warrant the foundation and support 
by state authorities of institutions properly equipped 
and independently endowed to carry on the work. The 
pharmacological university institutions which are car- 
rying the burden of education with their few and 
underpaid professors are entirely inadequate to cope 
vigorously with this problem. 

The greatest care and painstaking detail are of course 
paramount in importance in the development of this 
science. There must be the most thorough reliability 
in the work of the chemist in unraveling the structure 
of the compounds which he has prepared as well as 
in the work of the physiologist and physician in inter- 
preting the symptoms which are provoked. The tech- 
nique of the work is as yet in its developmental stage, 
and still leaves much to be desired. We may hope that 
in time many an obscure and hitherto inexplicable 
phenomenon will find its explanation. 

Especially is the greatest care also demanded in 
judging and interpreting the results of experiments. 
For example, it happens occasionally that a faint sug- 
gestion of an effect in the initial substance is very con- 
siderably increased by the introduction of a new group. 
The almost self-evident inference is that this new group 
is in itself responsible for such an increment in the 
observed effect. But this conclusion may be quite 
erroneous, since the influence of the new group may 
essentially depend upon the fact that it neutralizes 
another effect which predominated in the initial sub- 
stance, or that it, so to ‘speak, paralyzes the action 
of a group that obstructed the prominence of the de- 
sired effect. Thus, for example, there is formed from 
the mildly anesthetic benzoyl ecgonine, 


20 GENERAL CONSIDERATIONS 


Sey ; Halas 5 |< s CHCOOH 





| 
N—CH; CHOCOCsHs; 








| 
GHz CH CH2 


by alkylation the powerfully active cocaine; but ben- 
zoyltropine, 


CHe CH. CHo 





| 
N—CH; CHOCOC¢H; 








CHe CH GH2 


is also powerful in its anesthetic effect. Therefore, we 
‘can conclude that the alkylation of the carboxyl group 
in benzoylecgonine does not impart the anesthetic prop- 
erties to the compound; but it does neutralize the 
inhibitory qualities of the carboxyl group. There is a 
similar relationship between arecoline II and arecaidine I: 


I ARECAIDINE Il ARECOLINE 
CH CH 
H2C C-COOH H2G C-COOCHs3 
H2C CHe H2C CHe2 
N 
| | 
GHz CHs3 


It must be clear that in such cases only the most 
painstaking consideration of analagous cases in thé 
greatest possible variety can" lead us to a correct. inter- 
pretation of results. : 

Great care is likewise necessary in quantitative com- 
parisons of effects. The mode of distribution must be 
carefully taken into account. For example, we must 


GENERAL CONSIDERATIONS 21 


consider that differences in solubility may often account 
wholly or in part for deviations from the expected local- 
ization possibilities of a drug or poison. Add to this 
the fact that probably in the case of every substance 
ingested we must admit that a certain quantity is nec- 
essary before any effect will be noticeable. Comparisons 
of intensity of effect should be made only after passing 
this initial quantity. Especially is this consideration of 
importance in cases where the ingested substance is nor- 
mally present in the organism. Under such conditions 
a certain adjustment of the normal organism has been 
already established for the material in question. 

It is, of course, only in exceptional cases that we 
find monotropic substances. By this we mean _ sub-’ 
stances that are limited in action to one organ, or still 
more correctly, to one element of one organ. New 
difficulties and new complications in judging the relative 
strength of effect arise from the differences in the points 
of attack or action of substances upon the complicated 
higher organisms. The attempt has been made in more 
recent times to avoid this difficulty as far as possible 
by making the experiments on the lowest life forms, 
such as the unicellular organisms of bacteria, paramecia, 
yeast, sea urchin eggs, red blood corpuscles, ete. As 
one would expect, the results obtained in this manner 
are very well comparable among themselves. But it is 
clear that in order to reach conclusions which are applic- 
able to the higher animal organisms from the results 
with these lowest forms, it would be necessary to make 
an enormous number of different experiments on the 
most divers cell kinds. For there have been observed 
the greatest differences imaginable in, the effects of 
some groups upon warm- and upon cold-blooded animals. 
Not only that, but there have been found differences 


22 GENERAL CONSIDERATIONS 


of behavior in the most nearly related species. For 
example, the extraordinary diminution of the poisonous 
effect of p-aminophenyl arsinic acid by acetylization 
while observed in the case of the mouse is only slight 
in the case of other animals. In the case of the mor- 
phine derivatives, the only experimental results that are 
comparable with the effects on the human organism 
are those obtained on the organism of the cat. We 
must mention here the quite valuable investigations that 
have been made on isolated organs retained in their 
state of normal functions by means of an artificial cir- 
culation of blood. 

But there are sometimes individual differences even 
in the same animal kind. That such is the case even in 
the lower forms of life is shown by the occurrence of 
some trypanosome types that are immune to poisons 
through an established tolerance. In the higher forms 
of life and particularly in man, this phenomenon is ~ 
very strongly pronounced and very varied. It is known 
under such names as idiosyncrasy, tolerance and im- 
munity. Some substances have been observed to act 
differently under normal physiological conditions and 
under pathological conditions. Thus, quinine will re- 
duce the temperature of a fever patient from 3° to 4°, 
while the temperature of a normal person is only slightly 
lowered. Salicylic acid is powerfully active in this 
direction in cases of acute articular rheumatism, while 
it is but slightly active in other febrile affections and is 
inactive upon the normal body. 

Now, it will be quite evident that conditions are very 
complicated indeed when one wishes to act upon living 
organisms such as injurious parasites within another 
living being. Inner disinfection by chemical means 
in bacterial affections has remained, as is shown in 


GENERAL CONSIDERATIONS 23 


_ 


the case of the phenols, a pious hope, a consummation 
devoutly to be wished for. It is quite true that the 
specific serum therapy will have to be referred for its 
ultimate reasons to chemical effects, although the eluci- 
dation of the chemical processes herein involved is still 
in its very infancy. But we already know that in some 
cases of serum therapy we have to deal with the con- 
comitant action of lecithins and other lipoids, and per- 
haps soaps. The conditions seem to be more favorable, 
however, in the battle against animal parasites, where 
iodine, arsenic, and mercury compounds and certain 
dye-stuffs have been shown to be efficient in doses not 
injurious to man. In the case of dye-stuffs particularly 
there has been established a distinct relationship between 
constitution and effect upon the organism. 

Some substances do not act as such for themselves, 
but only through secondary products, which are formed 
from them in the organism. The knowledge of such 
transformations forms an important field of our study, 
a field, however, which we can but casually touch upon 
in this treatise. 


INORGANIC COMPOUNDS 


In the action of inorganic substances we have to deal 
with other considerations besides the local effects such as 
are produced especially by free acids and alkalies. There 
is above all the effect of the water, and in the case of 
salts, since these are either used in solution or dis- 
solved in the body, there are the various conditions 
dominant in solutions. The salts in part dissociate 

into their ions, and these, together with the undissociated 
galt, are the cause of osmotic pressure. According as 
the solution is hypotonic or hypertonic it will either 
cause a flooding of the tissues or will effect an abstrac- 
tion of water from them. In the case of hypertonic 
solutions, we have to deal with salt action in its proper 
sense, which manifests itself preponderatingly in an 
increase of diuresis! Further, the ions are the cause 
of. specific effects. Blake? in his investigations, which 
extended over several decades, determined that these 
effects are due essentially to the electropositive com- 
ponents. By directly introducing the substances into 
the circulatory systems of living animals, he arrived at 
the following conclusions: 

(1) The action depends only upon the kations, and © 
has only very slight connections, if any, with the anions. 

(2) In the same isomorphous group the activity bears 
a distinct relationship to the atomic weight, the in- 

1'gollmann, Am. J. Physiol., 9, 13, 454 (1907). 


2 Blake, Compt. rend., 1839; Proc. Roy. Soc., London, 1841; 
Am. J. Sci., 1874; Ber., 14, 394 (1881). 


24 


INORGANIC COMPOUNDS 25 


tensity of activity increasing with the atomic weight. 
The following groups are qualitatively equivalent: 


(a) Li, Na, Rb, Tl, Cs, Ag, (K and NHa do not 
fall in this series) ; 

(b) Mg, Fe, Mn, Co, Ni, Cu, Zn, Cd; 

(c) Ca, Sr, Ba; 

(d) Th, Pd, Pt, Os, Au. 


Blake characterizes these group effects in detail as 
follows: 

(a) Monovalent elements exert a powerful astringent 
or contracting action upon the capillaries of the lungs. 
They circulate through the nerve centers in greater 
concentration than through the lungs, and they exer- 
cise no appreciable effects upon the body capillaries. 

(b and c) The salts of all divalent elements cause no 
contraction of the capillaries of the lungs. They are, 
however, detrimental to the heart action, and if ad- 
ministered in sufficient quantity inhibit it entirely. 
In smaller quantities the substances of the magnesium 
group (b) act directly upon the hzemogastric nerve, 
and presumably they act indirectly, by a reflex action, 
upon the intestine nerve (nervus splanchnicus). The 
members of the calcium group (c) act upon the spinal cord, 
causing spasmodic contractions of the voluntary muscles. 

(d) The salts of the trivalent and tetravalent metals 
act principally upon the inhibitory as well as upon 
the vasomotor centers of the medulla oblongata. For 
the different valences of the same element there are 
characteristic differences in the compounds. In general, 
with increase in valence of the element there is an in- 
crease in the number of organs affected. Thus, ferrous 
compounds affect fewer organs than ferric, etc. 

Blake later arranged the elements in isomorphous 


26 INORGANIC COMPOUNDS 


series, according to their atomic weights and the degree 
of their toxicity. The following is his table, the atomic 
weights being taken by him from the international 
table for 1908: 








.- Lethal dose for 
Group. Element. Atomic weight. | 1 kgm. of animal 
body. 
(a) PALO ess a sles cee 7.03 i ee 
Rubidium. 2... 2.-; 85.5 0.12 
ORBIT 5 kao 95s 132.9 Ores 
Se eae 107.93 0.028 
ao eae eine apres 197.2 0.003 
(d) Magnesium........ 24.36 0.97 
PROBALY) oho ce 55.9 0.32 
IRICKION 5 i. 6 hin 3 dean 58.7 0.18 
CTA anes eg 8g 59.0 0.17 
Op ReE Oi. 6S is 63.6 0.17 
Zine 1 65.4 0.18 
Cadmium 2 112.4 0.085 
(c) TRMRUM <5 is ees aS 40.1- 0.50 
Strontium, 5... 5. 87.6 0.38 
Parity rk 137.4 0.08 
(d) Aduminumy...°. 3.00562... 271 0.007 
Toon: (OED as 25 55.9 " 0.004 
BSc 1 1 7 em eater eae 89 0.004 
Cerium (III)....... 140.25 0.005 
Cerium (IV)....... 140.25 0.062 
Torney 62. ss ss 232.5 0.034 
Lanthanum........ 138.9 0.025 
Didimium..; .-... .. =. 142 0.017 
Palladium ... . 65... 106.5 0.008 
Pistmum. i753; 194.8 0.027 














We may add that uranium with the high atomic weight of 238.5 is ex- 
Cay. poisonous.—Kobert, Arbeiten, 5, 1 (1890). ; ‘ 

1 Gallium with an atomic weight of 70 is according to Rabuteau slightly 
more active than zinc.—Rabuteau, Compt. rend. soc. biol., 35, 310 (1883). 

2 Compare Athanasiu aud Langlois, Ibid. 47, 391, 496 (1895). 


INORGANIC COMPOUNDS 27 


As before mentioned, potassium occupies, according 
to Blake’s investigation, an exceptional position, which 
he, as in the case of nitrogen, connected with deviations 
observed in the behavior of the spectrum. Sodium, on 
the other hand, does not fit into the series in a quanti- 
tative way. This exception on the part of sodium may 
be explained by the odd and peculiar position of that 
element as a special sub-group of the alkali metals in 
the Mendelejeff system. There is also another point 
of view, which we shall reach later, which will enable 
us to understand this peculiarity. Potassium and am- 
monium share with the other monovalent kations the 
property of acting upon the capillaries of the lungs. 
At the same time, they possess like the calcium group, 
with which they are both isomorphous, the property 
of contracting the voluntary muscles. Potassium is at 
the same time a powerful cardiac poison.! This same 
property is also observed to a certain degree to be 
possessed by czesium and rubidium. In this case then, 
the intensity of action increases with diminishing atomic 
weight. Therefore, contrary to the original formulation of 
Blake, but in accordance with the demands of the periodic 
system, potassium shows properties in common with the 
other alkali metals (excepting sodium). Furthermore, quite 
in accord with these facts, the ‘‘ typical ”’ element lithium 
has only the faintest suggestion of the cardiac effect.? 

Binet has carried out a more exhaustive investigation 
of the alkalies and alkaline earths? According to his 
experiments, both groups in common cause in the central 
nervous system a diminution of susceptibility for exci- 
tation and they also cause a disturbance in the power 
of contraction of the muscles. Preceding the latter effect 


1 Astolfoni, Arch. intern. Pharmacodyn., 11, 381 (1903). 
2 Botkin, Zentr. med. Wissensch., 1885, No. 48. 
’ Binet, Compt. rend., 115, 251 (1892). 


28 INORGANIC COMPOUNDS 


there are to be observed disturbances in respiration and 
in heart action. In the case of warm-blooded animals, 
these may cause death before the first general effects men- 
tioned above become appreciable. There are found some- 
times also (particularly in the case of barium and lithium) ! 
disturbances in the alimentary canal. Besides these 
differences we observe strikingly characteristic and dif- 
ferent effects for the chemical groups of the metals. 
Thus, the alkalies cause stoppage of the heart in diastole 
besides a motor inactivity through a general relaxation 
of the muscles. The alkaline earths, on the other hand, 
stop the heart in systole. Magnesium resembles the 
alkali group in that it stops the heart in diastole, but 
it is distinguished from that group in causing an early 
paralysis of the peripheral nervous system. In the 
case of mammals, barium is the most poisonous element 
of the group for heart action and respiration. It is 
further characterized by contraction effects. Calcium 
acts predominantly upon the central nervous system, 
producing a state of rigidity with retention of reflex 
excitability and sensibility. 

Lusanna ? investigated the action of metallic chlorides 
upon respiration and contractility in the faradic exci- 
tation of the frog muscle, using solutions isotonic with 
a 7 per cent sodium chloride solution, and arrived at 
the following results: 





Respiration | Respiration | Respiration 
depressed. | not affected. increased. 





Contractility destroyed.....}| Ca,Hg,Cu| K NH, Ba 
Ni, Co 
Contractility not affected...) Li, Mg Na, Sr 














1 Good, Am. J. med. sci., Feb., 1903. 
2 Bull. soc. méd., 1907, No. 4. 


INORGANIC COMPOUNDS 29 


According to Hébert! thorium, cerium, lanthanum, 
zirconium, aluminum, and magnesium are posionous for 
fish, plants, aspergillus niger, yeasts and soluble ferments. 
The toxicity increases from magnesium (atomic weight 
24.36) to lanthanum (138.9), to cerium (140.25), to chro- 
mium (52.1), to aluminum (27.1), to thorium (232.5). 
There can be seen no relation whatever in this case 
between toxicity and atomic weight. 

There have rather recently been discovered in the case 
of magnesium, some very peculiar effects which remind 
one of certain alkaloids. According to Meltzer 2 solutions 
of magnesium salts injected either subcutaneously, intra- 
venously or directly into the canal of the spinal cord 
cause anesthesia and retard respiration. Upon admin- 
istering large amounts, the tonus of the vasomotor 
center is impaired and somewhat before this the tonus 
of the pneumogastric center is so affected, and there 
is observed a deep general stupefaction with relaxation 
of all the muscles. Of practical importance is the 
statement of Meltzer that a deep general narcosis can 
be obtained with quantities that do not influence heart 
action, blood pressure, or respiration. According to 
different authors,® we have to deal with a curare-like 
action on the motor nerve ends while the sensory nerves 
are said to be not at all affected. On the contrary, 
Delhaye,* found that the diminution of excitability is 
manifested more quickly and more intensely in the 
sensory than in the motor nerve system—that in the 
former it is central and that it is curare-like only in 

1 Hébert, J. physiol. path. gén., 9, 217 (1907). 

2 Meltzer, Berl. klin. Wochenschr., 48, No. 3 (1906); Meltzer 
and Auer, Am. J. physiol., 21, 449 (1908). 

3 Wiki, Soc. biol., 60, 1008 (1906); Bardier, Soc. biol., 62, 


843 (1907). 
4 Delhaye, Bull. soc. roy. sci. méd. nat., Brussels, 1908, 72. 


30 INORGANIC COMPOUNDS 


regard to the motor endplates. According to him the 
injurious effect of this treatment upon respiration and 
upon the kidneys (resulting in a diminution of the 
quantity of urine and the appearance of albumin and 
cylinders in the urine), must preclude its therapeutic use. 

The fundamental characteristic effect common to man- 
ganese, iron, nickel, and cobalt, according to Wohlwill,! 
-is the production of capillary hypersemia of the stomach 
intestinal tract, and a consequent change in blood 
pressure. This together with a direct action on the 
central nervous system is probably responsible for the 
nervous symptoms exhibited under treatment with these 
substances. The manner in which these metals act is 
very similar to the action of arsenic. But they differ 
from arsenic in that they are not resorbed by the stomach 
and intestinal tract.” 

It is already apparent from what has been said, 
that the Blake laws are not universally valid. This 
is particularly noticeable in the case of the action of 
anions, an action which is practically denied by Blake. 
He himself, however, made a note of the difference in 
behavior of sodium orthophosphate and the pyrophos- 
phate which like the metaphosphate is poisonous. He 
sought to explain this difference by attributing it to 
greater hydrolytic dissociation, resulting in the liberation 
of a larger amount of free alkali. But this explanation 
will not hold. Differences similar to those found in the 
phosphoric acids also occur in the case of the vanadic acids. 

Blake’s negative results never referred to the halogens 
and cyanogen, although their specific effects are in- 
contestable. According to Bouchardat and Cooper, 

1 Wohlwill, Arch. exp. Path. Pharm., 56, 404 (1907). 


2Shumoff-Sieber, Biochem. Ztr., 2, 190 (1906). 
3 Frankel, Arzneimittelsynthese, 2d Ed., p. 5. 


INORGANIC COMPOUNDS 31 


the general tendency with the halogens is a diminution 
of effect with increase of atomic weight. But the rela- 
tionship is different in the case of the sodium salts. 
For here the fluoride is most poisonous. Then follow 
in order the iodide, bromide and chloride. Their com- 
parative toxicity may be judged by the following toxic 
doses: fluoride, .02 gm.; iodide, 8 gms.; bromide,: 10 
gms.; chloride, 40 gms. 

There is an essential difference in action between the 
halogen salts and the sulphates in that the former are 
easily resorbed, while the latter are resorbed only with 
decided difficulty with the result that the sulphates 
exhibit a specific saline action in the form of a purgative 
effect. 

According to Pauli! all ions act upon albuminous 
substances, but there is an antagonism or opposition 
between the two kinds. The kations precipitate such 
substances, while the anions exhibit a counter effect. 
The purgative action is related to this capacity for 
precipitating albumin. Thus, the purgative effect in- 
creases from the slightly astringent and laxative alkali 
salts to the heavy metal salts, which cause caustic and 
gastroenteritic effects.2. Among the anions themselves 
also, the counterprecipitation and accordingly the anti- 
purgative tendency varies, the halogens being most 
active in this respect. And of the halogens iodine is 
most effective, although it is exceeded by sulphocyanide. 

For salts of the alkaline earths the anions can be 
arranged in the order of the counter precipitation effect 
as follows: SCN>I>Br>NO3>Cl>CeH302. For 
salts of the alkalies the arrangement is reversed, viz.: 
CoH302>Cl>NO3>Br>I>SCN. The kations may be 


1 Pauli, Miinch. med. Wochschr., 50, No. 4 (1903). 
2 Hofmeister, Arch. exp. Path. Pharm., 24, 247 (1888). 


32 INORGANIC COMPOUNDS 


arranged in the order of their precipitating power as 
follows: Mg>NH4>K>Na.! 

But we must remark here that the total specific 
action upon the organism does not necessarily accord 
with the ion effect. This is strikingly illustrated by 
the action of alkaline earth ions in regard to the SCN 
action. The alkaline earths are not themselves precip- 
itants. Nor are the sulphocyanides of the alkalies. 
Yet the two acting together will cause precipitation 
of proteids. In living animals that have been moderately 
dosed with sulphocyanides a subsequent dosage of 
barium causes an acute sulphocyanide poisoning, while 
strontium causes a hardly perceptible increase in the 
sulphocyanide action and calcium has no effect at all.” 

In some other poison effects polyvalent kations can have 
an action antagonistic to that of the monovalent kations. 

A certain concentration of sodium ions is necessary 
for the contractive action of frog muscles,? the Medusa 
Gonionemus,* and fibers or strips of the heart muscle 
of Chrysemis Marginata.® But if the sodium ions (or 
in their place lithium, rubidium, or calcium ions) alone 
are present, then they have a poisonous effect. If 
frogs’ muscles are suspended in a pure 7 per cent solu- 
tion of sodium chloride, they attain in about an hour 
a state of rhythmic spasms or convulsions that con- 
tinues for twenty-four hours or longer.® Teleostier, Fun- 
dulus and its impregnated eggs die quickly in a pure 
sodium chloride solution on account of the osmotic | 

1 Pauli, Hofmeister’s Beitr., 5, 27 (1904). 

2 Pauli and Frohlich, Wien Akad. Ber., 115, III, Abt., June, 
1906. 

8 Overton, Pfliiger’s Arch., 92, 115, 346 (1902). 

4 Loeb, Am. J. Physiol., 3, 383 (1900). 

5 Lingle, ibid., 4, 265 (1900). 

6 Loeb, Festschr. fiir Fick (Beitr. z. Physiol.), p. 101 (1899). 


INORGANIC COMPOUNDS 33 


pressure of the sea water.! Gonionemus likewise stands 
a diminution of osmotic pressure better than a pure 
NaCl solution of normal pressure. This poisonous action 
of the sodium ions can be overcome by the addition 
of comparatively small amounts of trivalent kations. In 
the case of Fundulus and Gonionemus the poisonous 
effects are wholly destroyed by Ca, Ba, Sr, Mg, Pb, 


Co, Fe, Zn, Mn, Cr, Al, while they are in part removed 
by U and Th. There is no such action at all by Hg, 


It 


Cu, Cd, Ni, and Fe.? In the case of the frog muscles, 
the rhythmical convulsions or spasms are not stopped 
by Ba, Zn, Cd, and Pb, but they are stopped by K, 
notwithstanding the fact that it is monovalent. And 
further, in the case of Fundulus and Gonionemus, the 
presence of K ions is necessary, besides that of the 
divalent ion for a complete restitution of the normal 
function. The reason for this necessity of a definite 
equilibrium of ions must probably be found in the action 
of the ions upon those colloids which are necessary for life.4 

Herbst ° makes the observation that for the develop- 
ment of the eggs of Fundulus Mg ions are necessary as 
well as Na, K and Ca. Furthermore, he finds that the 
anions are not negligible, since chlorine, sulphuric acid, 
and carbonic acid ions are also necessary. To a lim- 
ited degree, however, substitution of these ions by 


1 Loeb, Am. J. Physiol., 3, 327 (1900); Pfliiger’s Arch., 80, 229 
(1900). 

2Ibid., Am. J. Physiol., 6, 411; oaiooek s Arch., 88, 68 and 93, 
246 (1902). 

3 Ibid., Pfliger’s Arch., 91, 248 (1902). 

4 Hieehex Biochem. Renite. ., 1, 497 (1903); Hoeber and Gordon, 
Hofmeister’s Beitr., 5, 432 (1904). 

5 Herbst, Arch. 4 Entwickl. Mechanik, 17, 306 (1904). 


34 INORGANIC COMPOUNDS 


chemically related ones may be made. Thus, for exam- 
ple, S203 may to some extent be used to replace SOa, 
Br to replace Cl, and Rb or Cs for K. Moreover, in 
some processes a certain excess of hydroxyl ions is 
necessary. 

The hemolytic action of human blood serum is un- 
affected by the addition of sodium chloride, potassium 
chloride, or lithium chloride, but it is destroyed by 
salts of the alkaline earths and also by an N/8 con- 
centration of potassium sulphate.! 

Mathews? emphasizes the importance of both ions, 
but interprets the results as a consequence of the dif- 
ferent solution pressures and not of the different valences. 
According to his theory the poisonous effect of any 
given salt is inversely proportional to the sum of the 
solution pressures of the ions. 

In interpreting the results of such investigations we 
must always consider that the poisonous effect of some 
salts may be prevented by a certain saturation of the 
cells with other and harmless salts. Thus, according 
to Lesne and Richet fils,? sodium chloride administered 
either simultaneously or previously protects the organ- 
ism to a very considerable degree from the injurious 
effects of potassium iodide, ammonium chloride, and 
even of some salts of alkaloids. But this does not 
hold true for all salts, and in many instances no appre- 
ciable results could be found in this direction+* 

We must also bear in mind that a tolerance already 


1 Hektoen, Zentr. Bakteriol., 35, 357 (1904). 

2 Mathews, Am. J. Physiol., 10, No. 6 (1904); compare Pond, 
ibid., 19, 258 (1907). 

8’ Lesne and Richet fils, Arch. intern. pharmacodyn., 12, 237. 
(1903). 

4 Lesne, Richet fils and Noé, Soc. biol., 57, 99, 238 (1904). 


4 


INORGANIC COMPOUNDS 35 


established in the organism which is being used for 
experimentation on the effects of various inorganic 
salts, plays a very important part in the results obtained. 
To this fact, perhaps, may be attributed the exceptional 
position of sodium in the series, for this element consti- 
tutes the principal inorganic component of the fluids (or 
humors) of the body. In this connection we may also 
note, that, as we should expect, herbivora can stand potas- 
sium salts far better than can carnivora. In the case 
of calcium, the lower the stage of development of the 
animal kind, the greater is the tolerance toward this 
element. Also it is found that tolerance for calcium 
is more easily established in youthful individuals than 
in fully developed ones. For all substances which nat- 
urally occur in the organism there may be assumed a 
certain initial value or concentration which must be 
passed before the effects are really comparable or meas- 
urable. : 

Quite in agreement with the assumption of ionic 
effect or action in these physiological studies is the great 
importance of the degree of dissociation which is very 
decidedly pointed out by the investigations of Dreser ! 
and of Krénig and Paul? upon the bactericidal action 
of mercury salts. 

From all this discussion it is self-evident that the 
action of the individual elements is very largely. de- 
pendent upon the form of combination in which they 
act. The powerfully toxic effect of free phosphorus 
disappears at once when the substance is combined with 
oxygen, as even phosphorus suboxide is entirely lack- 
ing in toxic effect.2 Arsenic is most toxic in its hydro- 

1 Dreser, Arch. exp. Path. Pharm., $2, 456 (1893). 


2 Kronig and Paul, Zeitschr. esi Chem., 21, 414 (1896). 
3 Kobert, Therap. Gegenw., 5, 59 (1903). 


36 INORGANIC COMPOUNDS 


gen compounds and oxygen compounds, the trioxide 
having, of course, a particularly intense effect. The 
phosphonium and arsonium compounds have essentially 
the curare-like action of the organic quarternary am- 
monium salts. Finally, the compounds of the cacodyl 
type produce a characteristic arsenic effect proportional 
to the ease with which the organism can oxidize them 
to arsenic trioxide.! 

_/ The complex ions containing cyanogen with iron have 
an action not at all similar to their action as more 
simple ions. This point is clearly shown by the fer- 
rocyanides, ferricyanides, and sulphocyanides. Further- 
more, the different action of a single element with different 
valences may find its explanation in the difference of 
the corresponding ions. 

Above all, although the ionistic conception has been 
sufficiently justified by other experiences, we must men- 
tion the difference in behavior ordinarily to be looked 
for when an element is bound up in organic non-elec- 
trolytes. The specific action of an element in such a 
condition can only be expected after its transition into 
the ionic state, and, therefore, it must generally come 
into play in a slow, mild, and continuous manner. 

An example of such an effect has already been men- 
tioned in the discussion of the cacodyl compounds. 

The same explanation seems to hold in the case of 
compounds which have been recently accepted and 
much used of the type of p-aminophenyl arsinic acid. 
This substance is found in trade under the name of 
Atoxyl, and was formerly erroneously supposed to be 
meta-arsenous acid anilide. 

While we are discussing the organic arsenic compounds 
it may not be out of place to devote some space to a 

1 Kobert, l.c.; Martinet, Bull. gén. Therap., 155, 70 (1908). 


INORGANIC COMPOUNDS 37 


consideration of a little of their history, and the path 
which has led to that most recent compound which 
has caused tremendous excitement even outside the. 
scientific world—salvarsan. 

As early as 1837 Bunsen observed that cacodylic acid 
seemed to be less toxic (for frogs) than inorganic arsenic 
compounds. But Lebahn showed in 1869 and H. Schulz 
in 1879 that cacodylic acid, dimethyl arsinic acid 
(CH3)2AsOOH and also diphenyl arsinic acid are deadly 
poisons for warm-blooded animals, although slower in 
action than the inorganic arsenic compounds. Hefter, 
Kobert, and others arrived at the conclusion that such 
compounds act in proportion to their mineralization in 
the organism. There were various such compounds pre- 
pared and introduced for use; but the one which served 
as the starting-point for Ehrlich’s investigations is the 
afore-mentioned Atoxyl. It was soon observed that the 
various compounds prepared did not act entirely as if 
their effect depended upon mineralization alone. In fact, 
they were observed to have specific effects against infec- 
tious diseases. This was first observed in the case of 
trypanosome diseases. Thereupon arsenic returned to 
the first application which it had as a popular remedy 
against recurrent fevers or malaria. Its usefulness against 
sleeping-sickness and other trypanosome diseases was 
determined in the French colonies by Laveran and Mesnil. 
Thomas, and later Robert Koch used atoxyl for com- 
bating the sleeping-sickness. A serious hindrance to 
its usefulness, however, was the pronounced side-effects 
and the slowness and uncertainty of the cure. It was 
then to be hoped that the effect upon the parasites 
might be increased and the effect upon the host de- 
creased. The necessary changes in the constitution of 
atoxyl were made clear when Ehrlich and Bertheim 


38 INORGANIC COMPOUNDS 


discovered that the constitution ascribed to atoxyl was 
incorrect and that it is the mono-sodium salt of the long- 
known p-aminopheny! arsinic acid, NH2CgH4AsOzHae, 
which is designated arsanilic acid. The first step in 
the variation of amino compounds is usually to introduce 
acid radicles. The introduction of acetyl gave a prep- 
aration called arsacetine, the sodium salt of acetyl arsan- 
ilic acid. This was effective and little toxic for some 
animals, particularly mice; but was not suitable for 
use upon man, A better compound was found when 
the acetyl radicle was attached to the amino group 
by means of the methyl instead of carboxyl. This 
gave arsanilacetic acid, AsO3H2CsHs—NHCH2COOH. 
It was then found that trypanosomes in vitro were not 
killed by this compound, but by its reduction products, 
and that probably, as in the organic compounds of 
pentavalent arsenic, the real effect is due to a reduction 
in the organism to trivalent arsenic. Among such tri- 
valent arsenic compounds which were found to be power- 
ful against protozoa, but only slightly toxic for the 
higher organisms are the derivatives of amino-phenyl- 
arsen-oxide, NH2—CsH4—AsO, and derivatives of diam- 
‘ino arsenobenzol, NH2—CgH4—As=As—CgH4—N He, 
particularly arsenopheny! glycine, 


As—C,g H4—NH—CH2—COOH 


| 3 
As—Cg H4—N H—CH 9—COOH 


The next. step that was taken was a further introduction 
of substituents in the benzol ring. It was found that 
ortho substitution of most groups impaired the effect; 
but halogen increased it. About the next advance was 
to try some of the trypanocides upon spirille diseases. 
Atoxyl was tried upon cases of syphilis. Its close 


INORGANIC COMPOUNDS “39. 


derivatives were also tried, but in general the side effects 
are too great, compared with the advantageous action. 
The benzol sulpho derivative of atoxyl, however (which 
is called Hectine), and the mercury salt of arsanilic acid 
are said by some to be effective. It was next found 
that a powerful spirillocide was obtained by replacing 
with hydroxyl the amino group of di-para-aminoarsen- 
obenzol. This gives para-arsenophenol. Then the most 
effective substance was found by introducing amino 
groups in the ortho position to the hydroxyls in arseno- 
phenol. This gives dioxy-di-amino-arsenobenzol, whose 
hydrochloride is Salvarsan. 








HN 


As As 
| 

NHg 
| 


| 
OH | OH 


This compound is prepared by the nitration and 
subsequent reduction of para-oxy-phenyl arsinic acid, 
which is formed directly from phenol and arsenic acid. 
It was hoped and at first supposed that in this sub- 
stance we had an agent which at one fell stroke could 
kill all the protozoa in the organism, and thus avoid 
the ‘possibility of some of them becoming immune. 
But results have seemed to show that in some cases 
either some spirochete are relatively immune to the 
arsenic from the start or they are protected from its 
action by their location. Doubtless there are many 
cases that are promptly and permanently cured by 
salvarsan, as there are also many that are curable by 


40 INORGANIC COMPOUNDS 


mercury. In other cases, perhaps it is necessary to 
adopt a method previously indicated by Ehrlich—namely, 
that of combination therapy. 

The disadvantages, which occasionally accompany the 
use of salvarsan are attributed by Ehrlich to its in- 
stability toward atmospheric oxygen. Neosalvarsan is 
the result of an attempt to avoid this deterioration due 
to the attack of oxygen. Salvarsan was combined with 
sodium methanal sulphoxalate. This compound dis- 
solves readily in water with a neutral reaction to litmus, 
seems to be less toxic and more easily tolerated than 
salvarsan, and produces less injurious side effects. 

In cases where the element itself in non-ionized form 
is active, as for example in the case of iodine, it seems 
that the effect is dependent upon a dissociation or 
breaking down into elementary form, which is somewhat 
similar to ionization. 

But sometimes it seems to be just certain organic 
compounds of inorganic elements that exercise a peculiar 
and specific effect. In such cases, of course, for the 

attainment of this particular effect, the use of such 

- compounds is from the beginning clearly indicated and 
to be expected. For example, such is pre-eminently 
the case for many iodine compounds. After a sub- 
stance containing iodine had been extracted from the 
thyroid gland and had been recognized as its active 
constituent then iodothyrine, iodogorgonic acid, ete., . 
obtained from this secretion were used to obtain the 
specific effects desired. 

The advantages of the halogenized fats (Iodipine, 
Bromipine), and of the salts of the halogenized fatty 
acids (Sajodine, Sabromine) may be due essentially to 
their milder and long continued action on account of 
the necessity for a preliminary ionization. There is, 


INORGANIC COMPOUNDS 4] 


however, the possibility that their advantage may be 
dependent upon a condition more favorable to resorp- 
tion and assimilation. Such favorable conditions for 
assimilation have also been assumed to hold for organic 
iron compounds and also in various compounds through 
which phosphorus is introduced into the organism. 
Through such an assumption a special importance or 
efficiency has been claimed for the lecithins, glycero- 
phosphoric acids, and particularly for Phytin, which 
is a double calcium and, magnesium salt of anhydro- 
oxymethylene-diphosphoric acid. Whether or not all 
these assumptions will hold must be considered to be 
still an open question. 

It is undoubtedly possible to cause the metals to 
penetrate further into the tissues if they are in com- 
bination in organic molecules than if they were in the 
form of electrolytes, because of the precipitating effect 
that such electrolytes have upon albuminoids. Thus, 
they may be employed to obtain results in otherwise 
unreachable places.'| The importance of many com- 
pounds of this class depends upon this property or 
ability for penetrating the tissues in an unprecipitated 
condition. In this connection may be mentioned as 
an example the wide use of certain organic silver com- 
pounds such as Argyrol. 

_ A special place in the science of medication is occupied 
by colloidal solutions of the metals. Since all influence 
of the anions is eliminated in such a case we may per- 
haps expect a particularly clear and undisturbed effect 
of the kations. It cannot yet be decided whether it 
is upon this fact that the professed great efficacy of 
these solutions in infectious diseases depends, or whether 
there is at the same time a catalytic effect. 

1 Compare Pauli, Wien. klin. Wochschr., 17, 558 (1906). 


42 INORGANIC COMPOUNDS 


At all events it is quite certain that all varieties of 
metal colloids are not equivalent. Luzzatto! has made 
tentative experiments upon the influence of various 
colloids upon the resorption of medicinal substances. 


1 Luzzatto, Arch. fisiol., 1905, II, 10. 


ORGANIC COMPOUNDS 


Aliphatic Series 


According to Lauder Brunton and Cash, hydrocar- 
bons act quite generally upon the nerve centers. In 
the aromatic series this action is principally confined 
to the motor centers, while in the aliphatic series it 
affects essentially the sensory centers. In the case of 
the aliphatic series there is a very pronounced narcotic ,- 
and anssthetic effect, whether the application is sub- 
cutaneous or by inhalation. According to a law pro- 
pounded by Richardson! this effect increases (in the 
paraffine series) with the increase in carbon content, 
of the molecule. Coincident with this narcotic effect, 
and in marked contradistinction to that caused by 
substances of the morphine group, there is observed a 
reduction of the reflex excitability. 

Naturally the increase in effect of the members of the 
series with increase of carbon content finds its limit’ 
in the physical properties of the substances. The high 
boiling paraffines of high molecular weight are practically 
without any action on the orgahism. This is easily 
understood, since substances of the paraffine series are 
hardly capable of resorption and consequently their 
entry into the organs is possible only by evaporation, 
and is therefore dependent upon their vapor tension. 


1 Richardson, Med. Times and Gaz., 1871. » 





44 ORGANIC COMPOUNDS 


For a given carbon content unsaturated hydrocarbons 
act more powerfully than saturated hydrocarbons. Thus, 
for example, ethylene is much more active than ethane. 
In this connection we must observe that the double 
bonds in a cyclic system have less effect upon the in- 
tensity of action than do the double bonds in an open 
chain. 

For example,Jet us consider the three hydrocarbons, 


Pent ane, CH3—C H2.—CH2—CH2—CH3 
CHs | 
Pental, C—=CH—CH3 
CH3 
and, 
CH=CH 
Cyclopentadine | — CHe 
CH=CH 


Of the three we find pental to be most active, 
cyclopentadine second, and pentane least active. 

Pental is perhaps the only body of this series which 
has found practical application. And we may remark 


' that it exhibits a grouping which has also demonstrated 


@ 


its efficiency in other series. This grouping is an arrange- 
ment of alkyl groups about a center. As we shall soon 
note, the ethyl group is in general considerably more 
powerful in its effect than the methyl group. Now then, 
we should expect to be able to increase the activity of _ 
this body considerably by replacing the methyl by ethyl 
groups and also still further by the replacement of hydro- — 
gens by alkyl radicles. 

In its fundamental character the narcotic action of 
the monobasic alcohols and their ethers, neutral esters, 
ketones, aldehydes and halogen derivatives is the same as 
for the hydrocarbons themselves. But the intensity of 
this action yaries widely and is quite decidedly deter- 





y 


od 


} 
( 


j 
j 


) 


’ side-€ffects, manifested by convulsive spasms of such 


ALIPHATIC SERIES 45 


mined by the nature of the compound and the sub- 
stituting group or element. | 

The halogen derivatives, and particularly the chlorine 
derivatives, show a very considerably greater hypnotic 


_ action than do the hydrocarbons. This increase in 


power depends, in the first place, upon the halogen 
content and is proportional to it. Thus, methane has a 
barely perceptible narcotic action. Monochlormethane 
is weakly narcotic, dichlormethane is still more powerful, 
and chloroform and carbon tetrachloride, as is_ well 
known, are both very powerfully active. Other effects 
besides the narcotic action also increase with increasing 
halogen content. | | 
A depression of the heart and vascular activity is 
hardly noticeable in the case of the hydrocarbon. But 
it is plainly apparent with the halogen derivatives and 
is proportional to the halogen content. Thus, Zoepffel 1 
found that the pulsations of a frog’s heart were stopped 
after the administration of chloroform in only one- 


* fourth the molecular concentration that was necessary 


for the same effect with dichlormethane. 
Dichlormethane and carbon tetrachloride do not fall 
perfectly into the series because they produce powerful 


~ violence that the narcotic action is forced into a position 


‘of secondary importance. This special action, also, 
bears a definite relation to constitutional differences in 
composition. For, if we conceive of the halogen deriv- 
atives of the hydrocarbons as being the halogen acid 
esters of the corresponding hydroxyl bodies, then, as 
Brissemoret ? showed, we can find a concordance between 
the actions of the hydroxyl compounds) as well as their 


1 Zoepffel, Arch. exp. Path. Pharm., 49, 89 (1903). 
2 Brissemoret, Bull. gén. Therap., 158, 657 (1907). 


@ 


46 ORGANIC COMPOUNDS 


alkyl ethers. Thus, formaldehyde and its acetals cor- 
respond to dichlormethane, while we have carbonic 
acid and its esters corresponding to carbon tetrachloride. 
Upon examining the other two classes of compounds, 
we find that methyl alcohol and methyl ether corre- 
sponding to monochlormethane, and ortho formic acid 
and its esters corresponding to chloroform, are, without 
exception, real anzesthetics or hypnotics. 

In the ethane series there are additional differences 
to be noticed, and these may be referred to the dis- 
tribution of the chlorine atoms between the two carbon 
atoms. ‘Thus, ethylene chloride and ethylidene chloride, 
although they both have the empirical formula C2H4Cle, 
show certain marked differences in narcotic effect and 
also in side effects. _ 

The bromine derivatives show actions adie similar 
to those of the chlorine derivatives. Ethyl bromide 
has found application as an inhalation anesthetic, and, 
although bromoform is not sufficiently volatile for this 
purpose, it has nevertheless been used for mitigating 
the paroxysms of whooping cough. 

According to Binz,! iodoform taken internally acts as 
a narcotic and hypnotic. Mulzer,? however, denies that 
this is the case for all animal organisms. Such an action 
was observed by him for dogs, but not for rabbits. But 
there comes strongly into play in the iodine-substituted 
compounds another very important effect, and that is — 
their antiseptic action. This has been generally attrib- 
uted to the demonstrable liberation of iodine from the 
compound in the organism.’ 
| With the substitution of hydroxyl for a hydrogen in 


1 Binz, Berl. Kii@@W ochache. $2, No. 7 (1885). 
2 Mulzer, Z. exp. Path. Ther., 1, 446 (1905). 3 
3 ef. Schiirhoff, Arch. intern. ‘Bhatinadodyn:; 14, 427 (1905). 


o 


am 


ALIPHATIC SERIES 47 


the hydrocarbons the conditions become exceedingly 
interesting. With a single substitution we have, of 
course, instead of the hydrocarbon a monatomic alcohol. 
This increases the hypnotic action of the compound 
sufficiently so that these alcohols are practically useful 
hypnotics. In accordance with the Richardson law, we 
find the action to increase with the length of the straight “ 
carbon chain. So the longer the CH chain is, the greater 
will be the increase in hypnotic effect when the monatomic 


alcohol is formed. Furthermore, the secondary alcohols 


show a greater hypnotic effect than the primary alco- 


' hols, and the tertiary alcohols exhibit a still more power- | 
.ful action. In these latter, particularly even more than 


in the secondary and primary alcohols, there is to be 
observed a specific influence of the ethyl group. For 
example, it requires the administration of as much as 
4 gms. of trimethyl carbinol*to induce sleep, while even 
2 gms. of ethyl-dimethyl carbinol will induce a sleep— 
lasting from eight to nine hours. And the adminis- 
tration of only 1 gm. of tri-ethyl carbinol induces ten 
to twelve hours of sleep.! But the practical applica- 
tion of this latter substance for its hypnotic effect is 
precluded, because of the side-effects consisting of dif- 
ficulty in breathing when doses as large as 1 gm. are 
used and a powerful excitation for lesser doses. Thus, 
for practical purposes, the ethyl-dimethyl carbinol is the 
only one of these substances available for inducing sleep. 

This rather specific influence of the ethyl group which 
we shall later notice repeatedly seems to depend upon 
the fact that it has a special relationship to the 
nervous system. This has indeed been shown to be the 
case by color experiments of Ehrlich and Michaelis.? 


1 Schneegans and v. Mering, Therap. Monatsh., 1892, 331. 
2 Leyden-Festschrift. 


48 ORGANIC COMPOUNDS _ 


They showed that nerves were colored by dyes con- 
taining diethylamino groups, while they were not so 
affected by the corresponding methyl compounds. We 
must remark here, however, that this peculiarity of the 
ethyl group holds only in comparisons with the methyl 
group. Propyl groups we shall find equivalent to, or 
even stronger than ethyl groups in a given series. But 
we also find that the alkyl compounds of higher molec- 
ular weight are excluded from practical application— 
not because their narcotic effect is too weak, but because 
their undesirable secondary effect is too strong. Thus, 
it appears from an investigation by Rather! that we 
have the following relative toxic values as measured 
by the paralysis of conductivity for centripetal stimulus 
in a frog. 





Point of stimulation. CH.0 C2Hs6O C3:HsO CsHi0O | CsHwO 





Ischiadicus....... 1 a 18 36 =| 120 
Cornea: Soh oe: 1 3 30 90 225 
CU SERIO eas eet eR 1 2 5 20 50 

















There is likewise found a regular increase in action 
from methyl to ethyl to propyl alcohols in their action 
upon ciliated tissue and motor nerve fibers? on the 
development of moulds? and of sea urchin eggs.4 : 

In regard to that part of the influence which is due 
to the physical properties of the substance, we must 
refer to the general part of this work. 

We have already noted that the substitution of hydro- 


1 Inaugural-Dissertation Tiibingen, 1905. 
2 Breyer, Pfliiger’s Arch., 99, 481 (1903). 
8 Twanhoff, Zentr. Bakteriol. (I1), 18, 1389 (1904). 
4¥Fuhner, Arch. exp. Path. Pharm., 59, 1 (1908). 


ALIPHATIC SERIES 49 


gen by halogen in the hydrocarbons increased the nar- 
cotic power of the compound. The same _ condition 
holds in the case of alcohols. 

As a practical result of this knowledge we find a product 
put upon the market by the Elberfeld Farbenfabriken 
under the name of Isopral. This is trichlorisopropyl 
alcohol. 

When several hydrogen atoms of the hydrocarbon 
are substituted by hydroxyl groups we must distinguish 
two different sorts of results. In the first place, if the 
substitution takes place on the same carbon atom, 
then the narcotic effect is either maintained or strength- 
ened. The aldehydes and ketones (if we disregard their 
other properties) are decided narcotics. The same thing 
is true, as we have already mentioned, for ortho formic 
acid, acetic acid and their esters. But if the substitu- 
tion takes place on different carbon atoms the result 
is different. For the polyatomic alcohols as well as 
the oxyaldehydes (aldoles) and the oxyketones are 
lacking in hypnotic power, and this lack of power is 
proportional to the number of hydroxyl groups present. 
But the accumulation of alkyl groups about the carbon 
atoms which bear the hydroxyl groups seems to effect 
a compensation, or neutralizing of the action of the 
hydroxyl groups. Thus, some pinacones have been 
found to be active. Here again the favorable influence 
of the ethyl groups is clearly noticeable. For example, 
the dose of methyl pinacone, 


CH, GH 
>ccoH—COH< 
CH” Gis 


required to produce sleep is 10 gms., while only 2 gms. 
are required in the case of methyl-ethyl pinacone, 


50 ORGANIC COMPOUNDS 
CH, CH, 
C(OH)—COR 
2H5 CoHs5 


and finally, only 1.5 gm. of ethyl cours 


ee _, pocom—comng 


In general, the effect of the hydroxyl group remains 
unaltered or at most only slightly modified when an 
alkyl group is substituted for the “‘ typical”? hydrogen 
atom, although such a substitution causes the sub- 
_ stance to be more resistant toward the organism. ‘Thus, 
in a very general way we can see a similarity in the 
action of ethers and acetals to the action of their funda- 
mental compounds. But there is a series of important 
exceptions to this general rule which, however, concern 
chiefly the compounds of the aromatic series, 


Aldehydes and Ketones 


Even acetaldehyde shows a distinctly hypnotic action. 
This effect is exhibited in a greater degree by the poly- 
meric paraldehyde (C2H40)3 which at the same time 
causes less preliminary excitation than the simpler body. 
The acetals are feeble sleep producers, and there is no 
appreciable difference in this respect between methylal 
and the ordinary acetal. Analogous to the difference 
in behavior of acetaldehyde and paraldehyde is the dif- 
ference between the corresponding sulphur ste Sage 
thioaldehyde and tri-thioaldehyde. 

The influence of the substitution of halogens is again 
very prominently shown in these compounds.  Tri- 
chloracetaldehyde, (Chloral) or rather, Chloral hydrate, 


ALIPHATIC SERIES 51 


which is easily formed by the addition of water, is a very 
strong narcotic. It was Liebreich who introduced this 
first synthetic therapeutic agent (chloral hydrate) and 
thereby gave a tremendous impulse to the modern 
synthesis of such substances. He thought that its action 
was dependent upon the splitting off of chloroform, 
a reaction which is easily accomplished outside the 
organism by means of alkaline liquids. Accordingly, 
he considered as useful hypnotics all those compounds 
which have three chlorine atoms, firmly enough bound 
to one carbon atom to make possible the formation 
of chloroform. Although this hypothesis resulted in 
such a beautiful practical success, it can hardly claim 
any advocates to-day. For it is very questionable 
whether there are at all appreciable quantities of chlor- 
oform produced in the organism from chloral hydrate. © 
The larger part of it, as von Mering has showed, is 
converted into trichlorethyl alcohol, which conjugates 
with glucuronic acid, with the resultant formation 
of urochloralic ’ acid or trichlorethylglucuronic acid 
(CeClsH2-CgH9O7). Trichlorethyl alcohol itself acts 
exactly like chloral. On the other hand, the trichlor- 
acetic acid obtained by the oxidation of chloral is said 
to be without hypnotic properties. Although there have 
been observations to the contrary, they have been at- 
tributed to impurities in the sodium trichloracetate 
used, a substance which it is exceedingly difficult to 
obtain in a pure state. Now trichloracetic acid will 
split off chloroform as easily as will chloral, and under 
similar conditions. So Liebreich’s hypothesis must be 
considered untenable. . : 
_ Chloral has certain disagreeable effects, especially an 
irritant action which depends upon the presence of the 
aldehyde group. Therefore, it was natural to make 


52 ORGANIC COMPOUNDS 


use of the capacity of this group for easy reaction and 
to prepare compounds which it was hoped would be 
devoid of these disagreeable side-effects. ‘Such a series 
of derivatives has been made, and the results of an 
examination of these substances are interesting because 
they support the assumption that the aldehyde group 
participates in the action of chloral hydrate. For of 
these derived bodies the only ones which had the desired 
hypnotic action were those from which chloral could 
be easily reproduced. The more stable ones were not 
only less active as hypnotics, but were often strongly 
toxic. The result is that attempts in this direction have 
been fruitless, for in those cases where the desired hyp- 
notic effect was attained the undesirable action of chloral, 
especially the effects upon the heart and respiration, 
was correspondingly pronounced. There are, however, 
some of the compounds which have the advantage of 
avoiding the disagreeable effect upon the stomach, 
because the chloral splits off in the lower parts of the 
digestive tract. We may thus classify the following 
from the compounds which have been prepared: 
1. As sufficing for hypnotic effect: 

Chloralamide, CCls—CH(OH)—NH—CHO, or more 
correctly chloral formamide, splits off chloral hydrate 
slowly in the organism.! 

Chloralose or anhydro-gluco-chloral is a condensation © 
product of chloral and glucose.” 

The poison effects quite recently observed in the use 
of this substance are said to be due to the fact that 
there is formed beside the useful chloral, varying amounts 
of another substance, parachloralose, which has no 
hypnotic action, while it does produce nausea, rise in 


1y. Mering, Therap. Monatsh., 1889, 565. 
2 Heffter, Ber., 22, 1050 (1889). 


ALIPHATIC SERIES 53 


temperature, and a subsequent subnormal tempera- 
ture.! 

Very similar to this seems to be the case in the con- 
densation products of chloral with pentoses.? 

Dormiol or dimethyl-ethyl-carbinol-chloral is a con- 
densation product of chloral and amylene hydrate.® 

Hypnal or monochloral antipyrine.4 

Compounds with the ortho forms, as 

Chloran, an addition product of acetone-chloroform 
with chloral, 


JOH 
CCls—CO—C—CH2—CCls. 
\CH3 


2. As insufficient for hypnotic effect: 

Chloral ammonium, or trichloraminoethyl alcohol, 
CCls3-CH(NH2)OH.4, 

Chloralimide, CCl3-CH=NH. 

Chloralcyanohydrate, CCl3-CH(OH)CN, which de- 
composes with difficulty with the formation of hydro- 
cyanic acid. 

Chloral acetone, CCl3-CH(OH) -CH2-CO-CHs3.6 

Monochlorurea and dichlorurea. 

Chloralurethane, CCl3-CH(OH)NH-COe2-CeHs. 

Chloral acetophenone, CCl3-CH(OH)-CH2:-CO-CeHs, 
which is converted in the organism to trichlorethylidene- 
acetophenone, CCl3-CH=CH-CO-Ce6Hs. 

Chloral acetophenoneoxime. 

Of the higher homologues of chloral the butyl chloral, 

1 Mosso, Chloralosio e Parachloralosio, Genoa, 1894. 

2 Henriot and Richet, Semaine médic., 1894, No. 70. 

3 Fuchs and Koch, Miinch. med. Wochschr., 1898, No. 37. 

4 Hertz, Therap. Monatsh., 1890, 243. 


5 Nesbitt, Therap. Gaz., 1888, p. 88. 
6 Konigs, Ber., 25, 794 (1892). 


54 ORGANIC COMPOUNDS 


CClsg-CH2-CH2:CHO, acts very much like ordinary 
chloral. A condensation product of this body with 
pyramidone which, put upon the market under the 
name of Trigemin, has been recommended by Overlach 
for use in cases of neuralgia, especially neuralgia of the 
trigeminus. 

The ketones in general possess hypnotic properties, 
which appear most distinctly and prominently empha- 
sized above the side-effects when there is an ethyl group 
in the compound. Thus, dimethyl ketone causes, coin- 
cident with a hypnosis like that observed in drunk- 
enness, an excitation of the heart and a subsequent 
paralysis of the central nervous system.” But diethyl 
ketone is a real and correct sleep producer with no = 
effect whatever on the heart action. Similar, but less 
pronounced, is the action of dipropyl ketone. The 
aromatic ketones, such as benzophenone, act less power- . 
fully than the aliphatic ketones, and, ranking between 
the two in physiological activity, as we should expect, 
are the mixed ketones of the type of acetophenone. 
And in this series of compounds the intensity of the 
action is essentially determined rather by the nature 
of the aliphatic component group than by the aromatic 
group. According to Fuchs and Schultze! the ketoximes 
are more intense in hypnotic action than the related 
ketones; but they have at the same time a harmful 
effect upon the digestive system. 


Acids and Their Derivatives 


The fatty acids exhibit a hardly perceptible narcotic 
action. Here, as in other cases, the carboxyl seems to 
VY reduce the effect of the compound. For when this 


1 Fuchs and Schultze, Miinch. med. Wochschr., 51, 1102 (1905). 


ALIPATHIC SERIES 55 


group is replaced, as by an alkyl or by an amide group, 
the action is again more pronounced. There is to be 
observed in this case, again, within certain limits, an 
increase of effect with increased carbon content. Thus 
for example, certain esters and amides of valerianic 
acid are more active than the corresponding derivatives 
of acids of lower molecular weight. Hans Meyer! was 
the first to establish in the case of the aliphatic acid 
amides the fact that their physiological activity in- 
creased with their molecular weight and that at the 
same time the compounds increased in solubility in ether 
and fat. According to Harrass,? the administration of 
amides is aceompanied not only by a narcotic effect, 
but also by phénomena similar to the spasmodic cramps 
caused by ammonia, which latter, however, are cer- 
tainly not due to the ammonia component alone. Both 
effects are increased by alkylation on the nitrogen. 
The only compound of this sort that has come into 
practical use is valerianic acid diethylamide, which is 
marketed under the name of Valyl. The introduction 
of alkyl groups upon the carbon atom of acetanilide 
results in only slightly active bodies; but if at the 
same time the third hydrogen atom is replaced by a 
halogen (e.g. bromine) there are formed some very 
effective sleep producers, such as diethylbromacetamide, 
ethylpropylbromacetamide, and dipropylbromacetamide. 
The diethyl compound, 
| CoH, 
C2H;—-C-CO-NHoe 
| Br* 


is used under the name of Neuronal.? — 


1H. Meyer, Arch. exp. Path. Pharm., 42, 109 (1899). 
2P. Harrass, Arch. intern. Pharmacodyn., 11, 431 (1903). 
3 Fuchs and Schultze, Miinch. med. Wochschr., 51, 1102 (1905). 


56 ORGANIC COMPOUNDS 


Under the name Adalin there has been introduced 
brom-diethylurea, which is recommended as a sedative 
and mild hypnotic, harmless to the heart and respira- 
ation in therapeutic doses. Such an action could have 
well been predicted for this compound. Although the 
general hypnotic action of the aliphatic compounds 
disappears when carboxyl is introduced, it reappears 
when this group is covered by an alkyl or amide group. 
Now the two things which increase this effect are the 
accumulation of alkyl, especially ethyl groups, and the 
introduction of halogen. Thus, although di-ethyl-dceta- 
mide, 

CoHs 
CH-CO-NHs 
CoH5 


is too weak to be therapeutically useful, if bromine is 
introduced in place of the remaining hydrogen, we 


have Neuronal, 
Co Hs Br 


eK 
CH”  ‘NCONH> 


which can be utilized as a hypnotic. It is to be noted, 
too, that in general the urea derivatives are more power- 
ful than the ammonia derivatives. Brom-diethyl-acetyl- 


urea, 


CoH; Br 


mod 
CoH’ ‘CO-NH-CO-NH> 


has the same relationship to Neuronal that urea has to 
ammonia. Another representative of the group is Brom- 
ural, which is an a-brom-isovaleriany! urea, 


B 
PP ano 


CH, \co.NH-CO-NH> 


ALIPATHIC SERIES 57 


This is constitutionally different from Adalin in that 
the bromine is attached to a different carbon atom 
from that which carries the alkyl groups. Now in general 
the methyl groups have less effect than ethyl; but the 
active dose of Bromural is no greater than that of 
Adalin. 

So we may be safe in saying that the location of the 
bromine seems not to be of great importance— or at 
least there is no one location which is essential. 

These compounds are valuable additions to our thera- 
peutic agents in that they are efficient but mild sleep 
producers without particular anesthetic action, and are 
said to be well tolerated in cases of cardiac disease. 

In the case of carbamide the alkylation of the nitro- 
gen may result under proper conditions in bodies with 
distinctly narcotic properties. As in the alcohol series 
we again see here the significance of the tertiary alkyl 
group. Although ureas into which have been intro- 
duced one or even more primary alkyl groups are lack- 
ing in physiological activity, nevertheless the tertiary 
bodies are strongly active—as for example tertiary 
amyl urea, 


and the tertiary heptyl urea which is very similar in 
structure, 


58 ORGANIC COMPOUNDS 


but more powerfully active. The tertiary butyl urea, 
on the other hand, 


is much less active. Therefore, we notice in these series 
again the influence on the one hand of the accumulation 
of alkyl groups and on the other hand the effect of 
increasing the weight of these alkyl groups. Later we 
shall return for a consideration of the urea derivatives 
of alkylated acids (Veronal group). , 

With the urethanes, H2N-CO-OR we find a narcotic 
effect by action upon the central nervous system with 
the great advantage that all the important body func- 
tions are undisturbed. Again in this series, more notice- 
ably in the lower members, the intensity of effect in- 
creases with the molecular weight of the substituting 
alcohol.!. The introduction of the acetyl into the amino 
group reduces the toxicity of the compound. The activity 
is greater in certain urethanes of secondary alcohols, 
and again we must emphasize the effect of increasing 
the number of alkyl groups present as, for example, 
in the case of methylisopropylcarbinol urethane, 


H2N—CO—OCH. CH 
2 \cHZ 3 


Nou; 


which is sold under the name of Hedonal.? 
Nitro compounds possess general toxic properties that 
are manifested in different ways. The nitrous acid esters, 


1 Binet, Rev. médic. de la Suisse rom., 1893, 540, 628. 
2 Dreser, Wien. klin. Wochschr., 12, 1007 (1899), 


ALIPATHIC SERIES 59 


which are isomeric with them, are so essentially and char- 
acteristically different in their physiological action that 
this action may be used for purposes of differentiation 
in cases of doubtful isomerism. This characteristic 
action consists of a dilation of the blood vessels. But 
there are observed differences of action which cannot 
be explained by constitutional peculiarities or carbon 
content, and are probably due to varying decomposition 
products. 

Even more marked are the differences in behavior 
observed in isomers of the cyanide compounds. Hydro- 
eyanic acid, which we may consider an _ isocyanide, 
with perhaps divalent carbon HNC, is about five 
times as toxic as dicyanogen N==C—C=N; but the 
characteristics of the effect are the same for both—that 
is, paralysis of the respiratory center in the medulla 
oblongata. Closely related to hydrocyanic acid are the 
organic isocyanides (isonitriles or carbylamines) R—N==C 
or R—N=C. According to Calmels,! methyl isonitrile 
is more poisonous than anhydrous hydrocyanic acid, while 
the ethyl compound shows a decided diminution in 
toxicity, being only about one-eighth as poisonous. 

The nitriles R—-C=N, on the other hand, although 
also poisonous, are essentially different in action from 
hydrocyanic acid. Acetonitrile inhibits the reflex exci- 
taticn and acts on some animals by inhalation as an 
anesthetic. Brissemoret? states that the only exci- 
tation is in the stomach and intestinal tract. According 
to Verbruegge * the toxicity of these compounds increases 
with their molecular weight. | 


1Calmels, Compt. rend., 98, 536 (1884). — 

2 A. Brissemoret, Soc. de biol., 60, 54 (1906). 

’ Verbruegge, Arch. intern. Pharmacodyn: 5, 161; Reid Hunt, 
ibid., 12, 447, 


60 ORGANIC COMPOUNDS 


In the cyanic acid compounds and thiocyanic com- 
pounds isomerism does not result in any essential dif- 
ferences of effect. Their action is somewhat similar 
to that of hydrocyanic acid, but very much weaker. 
The derivatives which contain oxygen seem to be more 
poisonous than the corresponding sulphur compounds. 
We may remark here, too, that in some instances the 
esters show toxic effects which are barely perceptible 
or not at all noticeable in the free acids and in their 
metal salts. 

Cyanogen in complex compounds seems to manifest 
its toxic effect only when there is a possibility of splitting 
off hydrocyanic acid in the organism, as, for example, 
in the case of sodium nitroprusside. 

We have repeatedly called attention to the influence 
which the accumulation of alkyl groups has upon the 
sleep-producing effect of substances. We have also 
noted the superiority of the ethyl over the methyl 
group in such compounds. Both of these points are 
again plainly brought out by the action of the group of 
sulphones. Their effect was at first accidentally discov- 
ered by Baumann and Kast! but was later subjected 
to a scientific investigation with the following results: 
Monosulphones, such as diethylsulphone, 

CoH; 


S02€ 
CoH; 


are inactive. The same is true of disulphones when 
the sulphone groups are attached to different carbon 
atoms, as in the case of ethylene diethylsulphone, 


CH2—SO2—CoHs 


CH,—SO:—CeH; 
1 Baumann and Kast, Z. physiol. Chem., 14, 52 (1890). 


ALIPATHIC SERIES 61 


But when the two sulphone groups are attached to the 

same carbon atom there is a hypnotic effect, and this 

effect is increased as ethyl groups are added. 
Dimethylsulphonethylmethane, 


ee OCs 
HW” \so.cHs 
shows a slight action, while diethylsulphonethylmethane, 
Laas SO2C2H; 
H” Cae. 


has a powerful hypnotic action, but at the same time 
a toxic effect. This latter effect disappears when the 
hydrogen of the central carbon atom is replaced by an 
alkyl group. 

Dimethylsulphondimethylmethane, 


ip 30.CH; 
Hee sors 


has practically no hypnotic action, while dimethylsul- 
phonethylmethylmethane, 


has a slight effect. The two isomers, dimethylsulphon- 


diethylmethane, 
cee a 
CoHs SOoCH3 


62 ORGANIC COMPOUNDS 


and diethylsulphondimethylmethane (Sulphonal), 


ry SO2CoH; 
oC 
CH3 SO2CoHs 


act equally powerfully, while diethylsulphonethylmethyl- 
methane (Trional), 


CH, _S0.CsH. 
Sc 
CH  8O.CoH; 


is more powerful and, of course, the strongest of all the 
members of the series is diethylsulphondiethylmethane 
(Tetronal), 


CoH; prOmeas 
>e< 
CoH; SOo2CoHs 


Now, quite in accord with our observations in other series, 
we find again that the replacement of the methyl group 
of sulphonal by alkyl groups containing more carbon 
atoms renders the body more powerfully active. We 
find the n-butyl is more active than iso-butyl. On the 
other hand, the action is arrested by the introduction 
of hydroaromatic and of aromatic groups and when two 
aromatic groups enter the same carbon atom, then, ac- 
cording to Hildebrandt,! the compounds become strongly 
toxic. The entrance of carboxyl or an amino group into 
the molecule of sulphonal also checks the hypnotic 
action of the compound, according to Th. Posner.” 
Particularly interesting is the law proposed by Baumann 
for this series of compounds. He claims that the action 
of the sulphones depends upon the ease with which they 


1 Hildebrandt, Arch. exp. Path. Pharm., 58, 90 (1905). 
2 Th. Posner, Chem. Ztg., 29, 1107 (1905). 


AROMATIC SERIES 63 


can be decomposed in the organism. But he says that 
this decomposability cannot be tested out in vitro. For 
it has been found that those very members of the series 
which are most easily attacked by chemical reagents 
will pass entirely undecomposed through the organism, 
while, on the other hand, those members of the series 
which are most resistant to reagents in vitro are de- 
composed in the body. 


The Aromatic Series 


In the aromatic hydrocarbons there is only a slight ~ 
indication of narcotic action. Their predominant effect 
is cramp excitant and paralytic. They also cause, 
according to Baglioni,! clonic spasms. These, however, 
are not preceded, as in the case of the phenols, by a 
stage of increased excitation, but on the contrary, by 
a state of profound paralysis. 

Chassevant and Garnier? established in the case of 
guinea-pigs three predominating symptoms of effect 
upon the nerves. These are cramps, muscle hypo- 
tonism, and hypothermism. Of these, the lowering of 
the heat production is a constant one observed from all 
derivatives, while the two other symptoms are variable. 

In the homologues of this series there is to be observed 
a great variation of the toxic effect, depending upon the 
kind and number of alkyl groups present. Methyl 
benzol (toluol), and ethyl benzol are more poisonous 
than benzol itself; but isopropyl benzol (cumol) is less 
poisonous. Repeated alkylation diminishes the toxic 
effect so that we find, for example, in benzol and its 
methyl derivatives the following rising scale of toxicity: 

1 Baglioni, Z. allgem. Physiol., 3, 312 (1904). 

2 Chassevant and Garnier, Arch. intern. Pharmacodyn., 14, 93 
(1905). 


64 ORGANIC COMPOUNDS 


Trimethyl benzols (mesitylene, pseudocumol)—di- 
methyl benzols (xylols)—benzol—methylbenzol (toluol). 
Among the xylols the toxic effect rises from the ortho 
to the meta and para compounds. 

Naphthalene causes a retardation of the respiration,- 
a depression of the temperature in cases of fever (but not 
normally), an increase of blood pressure in small doses, 
but a reduction of blood pressure in large doses. 

Contrary to the case of the aliphatic series, where 
the substitution by halogens exerted a very powerful 
influence, it is almost without significance in the aromatic 
compounds. 

The introduction of hydroxyl groups in these aro- 
matic hydrocarbons increases the cramp-producing action. 
In some cases, as for example, phenanthrene, it may 
be almost entirely lacking in the hydrocarbon, but ap- 
pear very distinctly in the hydroxyl derivative. At the 
same time, however, there is a change in the point of 
attack or action of the compound upon the organism. 
Benzol affects principally the brain, with a secondary 
action upon the cerebro spinal cord; but the phenols 
have quite the reverse action, affecting principally the 
cerebro spinal cord, while the action on the brain is 
very slight or almost lacking. So the phenols, since 
they increase the excitability of the motor mechanisms 
of the spinal cord, produce clonic spasms. Very large 
doses result further in paralyses (Baglioni). 

Increasing the number of hydroxyl groups in this 
series has the same effect upon this cramp-producing 
activity that it had upon narcotic activity in the case 
of the polyatomic alcohols of the aliphatic series. That 
is, it gradually disappears as the number of hydroxyl 
groups is increased. Thus, the three dioxy benzols still 
cause cramps in frogs; but the trioxy benzols produce 


AROMATIC SERIES 65 


only convulsions or spasmodic contractions. On the 
other hand, the substances become much more toxic 
in another direction, which is manifested in a lethargy 
and in tremors. 

Chassevant and Garnier,! however, state that the dioxy 
benzols are more poisonous than the phenols, while the 
trioxy benzols are less poisonous. According to Meyer,? 
Phloroglucide, 


is without pharmacodynamic effect. 

The degree of toxicity in the several series depends 
very largely upon the position of the substituting groups. 
In case of the dioxy benzols it rises from hydroquinone 
to resorcine to pyrocatechine. | 

In the organism, phenol is converted by synthesis 
into phenol sulphuric acid and phenyl-glucuronic acid, 
and also it condenses with partial oxidation to form 
dioxybenzols (pyrocatechin and hydroquinone sulphuric 
and glucuronic acids). The same is true for the homo- 
logues and substitution products. 

The action of naphthols is entirely analagous to 
that of the phenols. Of the oxyderivatives of the 
higher hydrocarbons, those of phenanthrene are of im- 


1 Chassevant and Garnier, Soc. biol., 55, 1584. 
2 See Herzig and Cohn, Wien, Monatsch., 29, 677, 


66 ORGANIC COMPOUNDS 


portance on accuunt of their relationship to the alkaloids 
of the morphine group. As has already been mentioned, 
they cause cramp effects. 

Similar to the behavior of the phenols is that of the 
quinones, as we should perhaps expect from the close 
chemical relationship. According to Brissemoret,! there 
are caused very excitant effects in the alimentary canal 
and on the outer skin by ordinary Quinone, 


O 
CoHi€ 
No 
Thymoquinone, 
CHs O 
CoHa€ 
C3H7 O 
and Naphthoquinone, 
: O 
CioHe 
G 


The same is true in the case of the natural product 
Juglon, which is oxynaphthoquinone, 


O 
Crolls(OH)€ 


Somewhat the same properties are manifested in the 
purgative effects of various anthra-quinone derivatives. 


1 Brissemoret, Soc. biol., 59, 453 (1905); 60, 175 (1906). 


AROMATIC SERIES 67 


CHRYSOPHANIC ACID 
OH CH3 


OH 


is found naturally in members of Rumex and Rheum 
species, as well as in the Cascara Sagrada. 

There is a closely related body which has found appli- 
cation in various affections of the skin. This is Chrysa- 
robin,! 


OH 
OH G CHS 





oH & 
i 


which, being a reduction product of chrysophanic acid, 
can easily be converted into that substance by oxidation. 
A similar relation holds between the related bodies 


ANTHRAROBIN and ALIZARINE 
on 22 0 
f 
OH- acs 
a < 
¢ 3 O 
H 


1 Hess, Ann. Chem., 309, 32 (1899). 


68 ORGANIC COMPOUNDS 


Related to chrysophanic acid are the various emo- 
dines of rhubarb, the aloe species, cascara sagrada, etc. 
Thus the emodine of the Chinese rhubarb has, according 
to Hess! the following formula: 


OH CHg3 


Brissemoret ? is authority for the statement that the 
essential condition for the action of these oxymethyl 
anthraquinones is the presence of an oxygen atom in 
the quinone binding. Ordinary benzoquinone has a 
purgative effect as has also resorufine. 


N 
O=CoHa€ >ColHs(OH) 


Accordingly, there does seem to be a necessity for at 
least one hydroxyl or quinone oxygen. 


PHENOLPHTHALEIN 


has, of course, been also found to be an effective .pur- 
gative. Even more strongly purgative than the natural 


1 Hesse, l. c. 2 Brissemoret, Soc. biol., 55, 48 (1903). 


AROMATIC SERIES 69 


emodines are some of the synthetic polyoxyanthraqui- 
nones. It was found necessary for practical application, 
however, on account of the violent side-effects of these 
substances, to convert them into compounds which are 
only gradually decomposed in the intestinal tract. Thus, 
Purgatine is the diacetyl ester of anthrapurpurine, 


OH 
CO 


HO— og 
Noe 
CO 


Exodine is a mixture of diacetyl-rufigallic-tetra-methyl 
ether, which acts only slightly, with the acetylpehtamethyl 
ether, which by itself would kave too violent an action. 


EXODINE 


Two other substances whose action is so violent that 
it must be moderated for practical application are the 
diacetyl-rufigallic acid and the rufigallic acid tetra- 
methyl ether. But if the hydroxyls are all completely 
closed by alkyl radicles as in the Seng aesa te ether the 
compound is ineffective.! 

In this connection we may mention that it is a general 


1 Ebstein, Deut. med. Wochschr., 31, 55 (1905). 


70 ORGANIC COMPOUNDS 


phenomenon that a given effect of a compound is dimin- 
ished by the alkylation or acylation of the hydroxyl 
groups.. The general effect is, of course, to make the 
compound less active chemically as well as pharmaco- 
logically. Thus we find that guaiacol, 


—OCH3 
—OH 


has an effect similar to that of phenol and pyrocatechol, 
but less poisonous; the maximum dose being for man 
1 gm. in the case of guaiacol and about one-tenth as 
great in the case of phenol. The toxicity, moreover, is 
still further diminished when the second hydroxyl group 
is also alkylated, as in the dimethyl ether Veratrol, 


OCH3 
OCHs 
The introduction of acid groups into the phenolic 


hydroxyl does not essentially change the physiological 
character of the compounds as much as one might at 


first expect. The reason for this is that the derivatives | 


so obtained are saponified in the organism and the 
hydroxyl group is again replaced. But the use of com- 
pounds of this sort has the advantage that the active 
substance comes into play gradually, that is, only as - 
fast as the saponification proceeds. Moreover, since 
this saponification takes place for the most part in the 
intestines, the stomach and upper digestive tract are 
protected from any chance secondary effects. | 


AROMATIC SERIES 71 


In some cases, however, alkylation of the hydroxyl 
group does have the opposite effect. For example, the 
dimethyl ether of resorcine is much more toxic than 
resorcine itself. Dimethyl sulphate is much more toxic 
than sulphuric acid. Such rather exceptional phenomena 
may perhaps be explained by saying that the introduc- 
tion of the alkyl group favors the selection of the sub- 
stance by the sensitive membranes. And in the cases 
which we are now considering, such a selection must 
depend very largely upon a change in the physical con- 
ditions of the membranes themselves. In some other 
- cases, moreover, we may have to deal not only with an 
increase in the main effect, but also with the removal of 
a disturbing influence which a hydroxyl, or particularly 
a carbonyl group, exerts upon the primary action of the 
substance. _ 

The influence of a carboxyl group quite generally 
appears in a retardation or inhibition of the primary 
effect of a compound. For example, when it enters 
an aromatic hydrocarbon it suppresses the action up to 
the point of causing a constant hypothermic effect, and 
too, it diminishes the toxic effect. If several carboxyl 
groups are attached to the nucleus, or if there are other 
substituted groups on the nucleus with the carboxyl 
group, then the strength of the carboxy] influence depends 
upon the relative position of these groups. This has 
already been shown in the case of the oxybenzoic acids. 
In the dibasic acids the toxicity diminishes from the 
meta to the para, to the ortho compounds, while in the 
toluic acids, according to Chassevant and Garnier it 
diminishes from the meta to the ortho to the para com- 
pounds. 7 

The sulphonyl] group possesses this inhibiting or retard- 
ing influence to a still more marked degree than the car- 


72 ORGANIC COMPOUNDS 


boxyl group. This is very largely and fundamentally 
the reason for the failure of some compounds which have 
been prepared by introducing the sulphonyl group, in 
order to render easily soluble some effective but difficultly 
soluble substances. 


Hydroaromatic Compounds 


The general effect of ring-formed ketones is a paralysis 
of the central nerve system and the motor nerve terminals. 
The latter are more affected as the size of the ring is . 
increased. Thus, the effect increases from pentanone 
or ketopentamethylene (1) to Hexanone or ketohex- 
amethylene (II) to Suberone or ketoheptamethylene 
(III). 

















I II 
CH> CH, 
nf oe HC” NCO 
HoC!__'cH. Hcl JcH, 
CH, 
KETOPENTAMETHYLENE KETOHEXAMETHYLENE 
Ill IV 
Cie—-—Gh-—CH, CH 
co Hc | \cu 
C: CH H3C-C-CH3| - 
Ha 2s | He ee 
KETOHEPTAMETHYLENE or C-CH3 
CyYCLOHEPTANONE CAMPHOR 


1 Jacobi, Hayashi and Szubinski, Arch., exp. Path. Pharm., 50, 
199 (1903). 


AROMATIC SERIES 73 


Camphor (IV), which is related to ketohexamethylene, has 
a cramp-excitant effect. It also stimulates the muscles 
of the heart to such an extent that it will neutralize the 
stoppage of heart action by muscarine in the case of the 
frog. In warm-blooded animals camphor also raises 
the blood pressure, even when the vasomotor nerve 
center is paralyzed by chloral hydrate. 








V VI 
_ C-CH(CHa)2 ct 
H.C CH, HC CH-CH; 
CH,-C-CH 
HC CO He2C CO 
THUJONE FENCHONE (Wallach) 
VII VIll 
CH CH, 
H2C/ | \C (CH). CH-CK op, 
CH H2C CH, 
FENCHONE (Semmler) CARVONE 


The behavior of Thujone (V) is similar to that of 
camphor, but Fenchone! (which according to Wallach 
has the constitution VI but according to Semmler has 
the constitution VII) and Carvone VIII ? have a different 
action. Carvone is a poison which has a violent cramp- 


1 Matzel, Arch. intern. pharmacodyn., 15, 331 (1905). 
? Hildebrandt, Z. physiol. Chem., 36, 441 (1902). 


74 ORGANIC COMPOUNDS 


producing action, which may perhaps be attributed to 
the double bond in the ring. A reason for ascribing this 
action to the double bond is that such an effect does 
not occur, for Menthone (IX) which is keto-hexahydro- 
p-cymene, nor for Pulegone X. 


IX ~*~ XI 
CH; CHs CHs CHe CH3 
| be in Va 
ae 1 C 
| 
CH C CH 
OC CH» OC CHo HC CH» 
H2C CHe H.C CHe HC CH> 
CH ie C 
| | 
CH3 CH3 CH3 
MENTHONE PULEGONE LIMONENE 


_ Nevertheless we must admit that the carbonyl group 
plays a very essential part in the physiological action, 
for we find only a very slight toxicity in Limonene (XI) 
which is quite similarly constituted except that the car- 
bonyl group is missing. 

Of the camphor derivatives, we find that monobrom 
camphor, as well as the oxidation products formed within 
the organism, show a cramp effect. On the other hand 


we do not find this effect in oxy-camphor. 

CO 

Csi | 
H(OH) 


which is a reduction product of camphor-quinone 


AROMATIC SERIES 75 


oat 


nor do we find it in borneol 


According to Pouchet and Chevalier! however, borneol 
and its esters (especially the iso-valerianate, which is in 
use under the name of Bornyval) have an effect upon the 
circulatory system similar to that of camphor. We 
find also that when the carboxyl group is introduced 
into this otherwise unchanged molecule with the forma- 
tion of camphor carboxylic acid 


CH—COOH 
ae 


the specific cramp effect is inhibited. It is a very remark- 
able fact that oxymethylene camphor 


shows no cramp effect, but paralyzes the central nerve 
system and heart; but oxyethylidene camphor and 
oxypropylidene camphor again show the typical cramp 
effect. This may be explicable by the fact that the acid 


1Pouchet and Chevalier, Bull. gen. de Therap., 149, 828 (1905). 


76 ORGANIC COMPOUNDS 


character of the first compound is vanishing in the 
high homologues.! 
According to Hildebrandt? Sabinol XII 


CH, CH, 


Eas 


He2C - 


Hi HOH 


v 


CHe 


SABINOL 


in spite of its close relationship to Thujone (V) has an 
effect different from all the other camphor-like bodies in 
that it causes hemoglobinuria and methemoglobinuria. 

In this connection a fact established in several cases by 
Hildebrandt * is particularly interesting, because it is 
in contradiction to the condition found in other groups. 
This is the fact that chain-form isomers of cyclic camphors 
are the more powerful. For example we may cite citral 
as compared with cyclocitral, nerol and geraniol as com- 
pared with cyclogeraniol. 

Concerning the influence of stereoisomerism there are 
somewhat divergent opinions. In the case of the stere- 
oisomers of camphor the qualitative similarity of effect 
is universally acknowledged. According to Langguard 


1 Bruhl, Ber., 37, 2179 (1904). 
2 Hildebrandt, Arch. exp. Path. Pharm., 45, 150 (1901). 
3 Tbid., Neuere Arzneimittel, p. 145 ff. 


AROMATIC SERIES heey 


and Maass! the excitant action of levo camphor is 
even greater than that of the natural dextro camphor, 
and racemic camphor is intermediary; but we find a 
more recent statement, and we must confess a more 
improbable statement, by Himildinen ? that the racemic 
and dextro forms have nearly the same activity while 
the levo compound is considerably weaker in effect. 


Inner Disinfection 


As is very well known, the phenols derive a special 
importance from the fact that they exert powerfully 
toxic effects upon the lower life forms (bacteria), that 
is, a so-called antiseptic action. In order to combat 
infectious diseases, as well as for prophylactic use, 
it would be highly desirable to be able to employ 
powerful internal disinfectants. But the unfortunate 
situation is that there is quite generally associated 
with the destructive action upon unicellular organisms 
a toxic effect upon the higher organisms also. And 
changes in the compounds which decrease the toxicity 
toward the higher form have the deplorable result of 
lessening the antiseptic properties of the substances. 
Thus, by the introduction of the carboxyl group into 
the phenol the toxicity is greatly reduced, especially 
if the introduction is in the meta or para position. But 
the ortho hydroxy acid (salicylic acid) is still more toxic 
than benzol and benzoic acid. Of the three isomers, 
then, salicylic acid alone still retains a rather consid- 
erable power for disinfection, and this is considerably 
lowered in comparison with phenol. 


1 Langguard and Maass, Therap. Monatsh., Nov., 1907. 
2 Himiéldinen, Chem. Zentr., 1908, II, 1451. 


78 


ORGANIC COMPOUNDS 





Change incompounds. 


Disinfection power. 


Toxic effect. 





of 
(Cl, 


. Introduction 
halogen 
Br). 


Introduction of 
alkyl groups in 
the presence of 


halogen in the 
molecule. 
Combination of 


two phenols. 
Direct (bi-phenols). 
By CHOH. 
By CHOR. 
By CO. 
By SOs. 


Increased, correspond- 
ing to the number 
of halogen atoms. 
Sixteen (16) mole- 
cules of tetrachlor- 
phenol, or, 2 mole- 
cules of pentabrom- 
phenol are equiva- 
lent to 1000 mole- 
cules of phenol. 


Increased. 

Tri-brom-m-xylenol is 
twenty times as act- 
ive as_ tri-brom- 
-phenol. Tetra-brom- 
o-cresol is sixteen 
times as active as 
tetra-chlor-phenol. 


Increased. 
Increased. 
Increased. 
Increased. 
Diminished. 
Diminished. 








At first diminished, 
then increased. For 
tri-halogen com- 
pounds it is about 
the same as that of 
phenol. Rises 
strongly for further 
substituted bodies. 
The cramp effect is 
diminished with in- 


creased halogen con- 
tent and finally 
stops. 


Compensates the toxic 
effect of the halo- 
gen. Tetra-brom-o- 
cresol has very little 
toxic action. 





This relationship, however, does not hold universally 


and without exception. 


Thus, after alkylation in the 


benzol ring with the formation of cresol, we find the 
antiseptic action greater than in the case of the simple 
phenol, while the toxicity of the compound for higher 


life forms is increased only slightly, if at all. 


In fact, 


AROMATIC SERIES 79 


for a frog, all the cresols are less toxic than phenol. 
For warm-blooded animals para-cresol is more poison- 
ous than phenol, while the ortho compound is about 
the same as phenol and meta-cresol is still less toxic, 
according to Tollens.! 

The admirable investigations upon this subject by 
Bechhold and Ehrlich ? disclosed the most varied changes 
in action by modifications of the compounds. These 
results:-are given in table on page 78 in so far as they 
have not been already treated. 

It was found, however, in attempting a practical — 
application of such compounds that the strong dis- 
infectant. power of the best disinfectants is very much 
modified in the blood serum. The result is that with 
these compounds, too, we must confess that inner dis- 
infection has not been successful. 


1 Tollens, Arch. exp. Path. Pharm., 52, 220 (1905). 
2 Bechhold and Ehrlich, Z. physiol. Chem., 47, 173 (1906). 


NITROGEN COMPOUNDS 


Ammonia and Its Simpler Derivatives 


Disregarding the excitant and caustic action of the 
free bases, the characteristic effect of ammonia is a cramp 
effect which causes in mammals the excitation of various 
functional tracts of the spinal cord and its branches. 
There results a temporary inhibition of respiration, more 
pronounced in the cramp intermissions. Larger doses 
cause, subsequent to the excitation stage, a paralysis of 
the nerve centers that ends fatally. Immediately after 
the injection of ammonia, there is a direct stimulation 
of the heart and a consequently large increase in blood 
pressure. Then follows a period of smaller increase in 
blood pressure, caused by vascular contraction, due to 
- a stimulation of the vasomotor nerve centers. At the 
same time there is a diminution in the pulse frequency, 
although during the first stage this is increased. 

In frogs the characteristic effect is manifested by strong 
excitation indicated by a reflex cry; then there follow 
convulsions and tetanus, and finally general paralysis. 

The replacement of hydrogen of ammonia by alkyl 
radicles immediately reduces the toxic action in a quite 
extraordinary manner. Moreover, the ammonia group, 
or all that remains of it, arrests the hypnotic action of 
the hydrocarbons. So we may consider the ammonia 
and alkyl radicles as mutually interfering groups. 
According to Hildebrandt ! the toxic effect in secondary 
amines increases with increasing molecular weight. 


1 Hildebrandt, Arch. exp. Path. Pharm., 54, 125 (1905). 
80 


NITROGEN COMPOUNDS 81 


The physiological character of the compounds is, how- 
ever, completely changed, as we shall see later in our 
discussion, when the alkylation is completed with the 
formation of quaternary ammonium bases. 

When an acid group is introduced, the characteristic 
ammonia effect is reduced to an even more marked degree 
than is caused by alkylation. This is the case whether 
the ammonia group is in combination with the oxygen 
of the carboxyl or with carbon. Both the acid amides 
and the amino acids of the aliphatic series are in general 
physiologically inactive. The amino acids of the higher 
series are to be regarded as albumin builders, and there- 
fore as belonging to the group of nutritive substances. 
An exception to the previous statement is found in car- 
bamic acid, NHz—COOH, which is poisonous. This 
acts as a°cramp-producing poison in a manner similar 
to ammonia, but somewhat modified. The cause of 
this exception is perhaps to be found in the ease with which 
the compound is broken down. For as soon as we make 
it more resistant to decomposition by the esterification 
of the carboxyl, we have formed urethanes, which are 
scarcely poisonous bodies. Furthermore in these com- 
pounds, the original ammonia effect has been so reduced 
or neutralized that the hypnotic action of the alkyl 
radicle is able to assert itself, and the intensity of its 
effect depends upon the character of the alkyl group.! 
In other words the original action has been suppressed 
sufficiently for the newly introduced action to characterize 
the compounds. Thus, in methyl-propyl-carbinol ure- 
thane (Hedonal), | ; a 


NHoe Fae at : 


1 Binet, Rev. médic. de la Suisse rom., 1893. 


82 ORGANIC COMPOUNDS 


on find a useful, mild sleep producer, which leaves all 
the life functions unaffected. 

A more recent compound which has been introduced 
under the name of Aponal is ethyl-dimethyl-carbinol 
urethane. This is probably still more powerful in action. 
It remains to be seen whether it possesses a diuretic 
action which has rendered the use of hedonal somewhat 
objectionable. These urethanes have, however, been 
claimed to possess a somewhat injurious action upon the 
heart and respiration. These effects, seem to have been 
satisfactorily overcome by a compound introduced as 
Aleudrin. This substance has, like Hedonal, the skele- 
ton of isopropylurethane; but the alkyl groups are 
chlorinated, 


CH2Cl 
CH2Cl 


CH-O—CO—NHg2 


The margin between the narcotic dose and the fatal dose 
is less for warm-blooded than for cold-blooded animals; 
but it is large enough for practical purposes. For man, 
sleep is produced by 0.5 gm. The body temperature, 
respiration, heart action and circulation are very little 
affected. Aleudrin appears to be a harmless sleep-pro- 
ducer of scientifically correct construction according to 
theoretical conceptions. 

The essential part played by the acid radicle residuum 
in the neutralization of the primary toxic effect is very 
clearly shown by a comparison of the amino acids and 
urethanes with the closely related aminoacetals. Ordi- 
nary aminoacetal, NH2CH2zCH(OC2Hs)2, produces a 
paralysis of the respiration in the same way that ammonia 
does.! 


1 Mallévre, Pfliiger’s Arch., 49, 484 (1891). 


NITROGEN COMPOUNDS 83 


This, of course, is quite in contrast to the. action of 
the methanes and amino acids. 

Of peculiar interest is the action resulting from the 
conjugation of the ammonia residual group and the aro- 
matic hydrocarbons, which are themselves cramp excit- 
ants. We observe then a change in the points of attack 
as compared with the action of ammonia. Aniline 
attacks not only the motor centers in the branches of 
the spinal cord, but also and more particularly those of 
the middle brain, where it causes first a passing excita- 
tion that manifests itself in convulsions, and then paraly- 
sis. The prominent symptoms are dizziness, drowsiness, 
and finally well-developed collapse. Aniline has the 
further effect of destroying the hemoglobin. There is 
also with aniline another effect which is therapeutically 
exceedingly important and that is the diminution of the 
body temperature.! 

As we have already seen, this action is peculiar to the 
aromatic ring; but it becomes pronounced only after 
certain substitutions have taken place.2 It is lacking in 
naphthalene and phenanthrene derivatives. In fact, 
there is even a marked rise in temperature after the 
administration of tetra-hydro-@-naphthylamine.? 

The other aromatic amines possess in a marked degree 
the injurious effects of aniline. The antipyretic effects 
are modified by the introduction of alkyl radicles into the 
molecule, the action depending largely upon whether the 
group enters in the ortho, meta, or para position. Thus, 
meta toluidine acts almost like aniline; but the ortho 
and para toluidines are very much weaker in action. 
The direct attachment of the amino group to the ring 

1Cahn and Hepp, Zentr. klin. Med., 1886, No. 33. 


2 Cf. Frankel, Arzneimittelsynthese, 2d ed., p. 241 ff. 
* Stern s. Bamberger and Filehne, Ber., 22, 777 (1889), 


84 ORGANIC COMPOUNDS 


seems also to be of essential importance for the anti- 
pyretic effect. For example there is such an action 
in only a slight degree in the case of benzylamine, 
CegHs—CH2—N He. 

In the basic triphenyl methane dyestuffs the poison 
effect increases in a marked degree with the introduction 
of alkyl groups, especially if this introduction takes place 
on the nitrogen. This effect, however, is still weak 
enough in pararosaniline to permit its use in the thera- 
peutic treatment of trypanosome diseases. The intro- 
duction of acid groups diminishes the poison action; 
but at the same time it also stops the trypanocidal power, 
as either the sulphonic or carboxyl group will entirely pre- 
vent this effect.! 

Naturally the same substituting groups which weaken 
the effects of ammonia have a like effect upon aniline. 
The next logical step was to determine whether such a 
diminution of action would be more in a desirable or in 
an objectionable direction. If acid groups (carboxyl 
or especially sulphonyl) are introduced into the ring the 
action is weakened in both directions, but the poison 
effect is strongest in the ortho derivatives, and it is still 
further increased by introducing methyl in the amino 
group.” ! ; 

The substitution of alkyl groups on the nitrogen has 
little effect, while acid groups have a quite noticeable 
effect. Thus, in the case of acetanilide (Antifebrin) the 
poison effect is sufficiently diminished and the antipyretic 
action sufficiently retained so that a practical applica- 
tion of the substance is possible. Nevertheless there 
remains enough of the ill effect to demand caution in 
its administration. The poisonous action is still fur- 


1 Ehrlich, Berl. klin. Wochschr., 44, 223 ff. (1907). 
2 Hildebrandt, Hofmeister’s Beitr., 7, 433 (1905). 


NITROGEN COMPOUNDS 85 


ther diminished in phenyl urethane (Euphorine), 
CesHsNHCOOC2H;; but the antipyretic efficiency is 
rather low. The aniline action is still further diminished 
in both directions in such cases as acetanilido acetic acid, 


and acetyl sulphanilic acid and its salts (Cosaprine being 
the sodium salt), 


NH-CO.CH; 
Coa 
SO,H 


Methyl acetanilide (Exalgine), 


Cott; 3 ne 
COCH 


is less desirable than acetanilide, but the nearly related 
diacetyldiphenylethylenediamine, 


CeHs CoH. 
N -CO-CHs3 


CH, -CO. NC 
CH.” 


CH 





is said to be less violent. 

Now it has been shown by the investigations of 
Schmiedeberg? that aniline and its derivatives are 
rendered harmless by the organism by the introduction 
of an hydroxyl group in a position para to the amino 
group. Paraaminophenol is much less poisonous than 
aniline, although it does cause the formation of methemo- 


1 Grassmann, Bull. soc. ind. Mulh., 1907, 4. 
2 Schmiedeberg, Arch. exp. Path. Pharm., 8, 1 (1878). 


86 ORGANIC COMPOUNDS 


globin. This effect is somewhat but not sufficiently 
reduced by the introduction of an acetyl group. Only 
when the. hydroxyl is esterified do we attain a point 
where the preparation is adapted for therapeutic use. 
The type of this sort of a compound is acetyl-p-amido- 
phenol ethyl ether or para-ethoxy acetanilide (Phena- 
cetine), : 
NH-CO-CH3 


CoHaC 
ae: 


Numerous derivatives have been prepared from phene- 
tidine, the base of phenacetine, as well as from Anisidine, 
which is the base of Methacetine, 


NHCOCH; 
sede ae 


the lower homologue of phenacetine. Such bodies have 
been subjected to careful physiological examination; 
but we will mention here only some of the preparations 
derived from phenacetine: 

1. Compounds derived by replacing the acetyl with 
other acid groups: 


Propiony! derivative (Triphenin), 
NH-CO-CH2-CH3 


CoH 
OCsH; 


Lactyle derivative (Lactophenin), 


NH.CO.CHOH-CHs 
CoH 
OC.H; 


NITROGEN COMPOUNDS 87 
Mandelic acid derivative (Amygdophenin), 
NH-.CO.CHOH.C.Hs 
Cola ) 
OC2H; 


Methylglycolic acid derivative (Kryofin), 
NH-CO-.CH2:0OCH3 
Cola 
OCoH; 


Acetylglycolic acid derivative, 


NH.CO.CH,0-CO.CH; 
CoH 
OC.H; 


Succinic acid derivative (Pyrantin), 


CO—CH> 
Ng | 
CoH CO—CH» 
OC.H; 


Citric acid derivative (Apolysin), 


COOH 
NH-CO.CHeC-CHe-COOH 
CoH | 
OCoH; OH 


The preparation which has been advertised under the 
name of Citrophene as citric acid triphenetidide is accord- 
ing to Hildebrandt ! essentially a citric acid salt of phene- 
tidine. 

1 Hildebrandt, Zentr, inn, Med., 16, 1089 (1895), 


88 ORGANIC COMPOUNDS 


Salicylic acid derivatives: 
(a) Salicylphenetidide, 
~/~NH-CO.CgH,OH 
CeH4 
NoosHs 


(b) Salicylic acetic acid derivative (Phenosal), 


NH.-CO-CH>-O0-CgHs-COOH 
Celie 
NocpH; 


(c) Acetyl salicylic acid derivative, 


NH-CO-CgHi-0-CO-CH; 
CoHsC | 
OCH; 


Acetyl-ethyl carbonic acid derivative (Thermodin), 


Amino carbonic acid derivative (Dulcin), 
NH-CO-NHo 
Col 
OC2H; 


Amino acetic acid derivative (Phenocoll), 


yo -CO-CH2-NHe 
CoHaC 
OC2Hs; 


2. Compounds derived by introducing acid groups 
in the ring (for the purpose of obtaining easily soluble 
bodies) : 


Phenacetine sulphonic acid. Phenacetine carbonic acid. 


NITROGEN COMPOUNDS 89 


3. Compounds obtained by condensation with alde- 
hyde and ketones: 


with salicylic aldehyde (Malakin), 
N-CH-CgH4-OH 


CoH 
OC.H; 


with acetophenone (the citric acid salt is Malarine), 


CHs 
NH=C 


CoH ou NOs 
OCsHs, 


with vanillin ethyl carbonate (Eupyrine), 
N : CH -CgH3(OCHs3) ‘O -COs -CoHs 
CoH 
OC2H; 


From an examination of these substances and similar 
preparations, and an observation of their physiological 
action, it has been possible to generalize somewhat and 
formulate some regularities in their action. In the first 
place, considering the substitution of the amino group 
of amino phenol by an acid radicle, this must be firmly 
enough bound so that it is not split off by the acid of the 
gastric juice (which amounts to two per cent hydrochloric 
acid). For if this happens there appear at once the unde- 
sirable and poisonous effects of para-phenetidine. On the 
other hand the binding of such an acid radicle must not 
be too firm. For it has been found that the only sub- 
stances of this group which have a good antipyretic 
action are those whose ingestion causes the appearance 
of the indophenol reaction in the urine. This color 
reaction which results from the action of a or 8 naphthol 
upon bodies with an amino group indicates that the sub- 


\ 
90 ORGANIC COMPOUNDS 


stances ingested must be capable of being broken down in 
the organism to compounds which have such a free amino 
group (for example para-aminophenol from para-amido- 
phenetol or para-phenetidine).| And observation has 
justified the conclusion that the intensity of the anti- 
pyretic effect is within certain limits proportional to the 
amount of para-aminophenol which is split off in the argan- 
ism. It is obvious, then, that too slow a process of splitting 
up the compound will result in failure of the desired effect. 
This was the result and its cause when the attémpt was 
made to use a combination with salicylic acid, a com- 
pound which has its own antipyretic and antineuralgic 
properties and therefore gave hope of forming particularly 
active preparations. The mandelic acid derivative is an 
example of another class of failures. The fundamental 
reason is the same—that is, there is too little splitting 
down of the compound in the organism; but the reason 
in this case is the slight solubility of the substance in the 
stomach and intestinal tract and the consequent insuff- 
cient resorption. ) 

So far as substitution of the hydroxyl group by alkyl 
radicles is concerned it does not pay to go higher than the 
ethyl group, as the antipyretic effect diminishes with the 
higher alkyl radicles. In fact the ethyl ether is some- 
what less active in this respect than the methyl compound; 
but the difference is so slight that it is more than offset 
by the desirable and very considerable diminution of the 
toxic effect. 

If we start with a body such as acetyl-p-amino phenol, 
which has a free hydroxyl group, and replace by an alkyl 
radicle the hydrogen which is still attached to the nitro- 
gen, the result is a series of inactive compounds. But 
if at the same time we alkylate the hydroxyl also, then 

1 Treupel and Hinsberg, Arch, exp, Path, Pharm., 51, 262 (1904). 


NITROGEN COMPOUNDS 91 


there is observed a narcotic effect, which is barely sug- 
gested in the parent body. In this respect the methyl 
and ethyl derivatives behave about alike, and with a 
further increase in the magnitude of the alkyl radicle 
all the effects seem to diminish.! 

An antipyretic effect is also to be observed in the urea 
derivatives of anisidine and phenetidine. The phene- 
tidine compound, which is para-ethoxy-phenyl carbamide, 
is particularly distinguished by an intensely sweet taste 
and has therefore been called Dulcin. This sweet taste 
is found in neither the lower compound (the methoxy 
body) nor in the higher homologues.” 

An effect similar to that of phenacetine, but weaker, 
is found with the isomeric compound acetyl-ortho- 
' phenetidine. 

Of the diamines the aliphatic bodies such as tetrameth- 
ylenediamine (Putrescine) , NH2—(CHe2)4—N Hag, and pen- 
‘tamethylenediamine (Cadaverine), NH2—(CH2)s—N Hoe 
are physiologically entirely inactive. In some derivatives 
in which one or both of the amino groups have been 
converted into imino groups by means of negative sub- 
stituents there appear strong toxic effects. 

Thus, for example, in the formaldehyde derivative of 
Cadaverine and in Sepsine prepared by Faust? this effect 
appears. ~ | 

The aromatic diamines, on the contrary, possess a rather 
strong toxicity, their peculiar action being a destruction 
of the coloring matter of the blood. According to Dubois 
and Vignon* meta-phenylene-diamine causes vomiting, 
cough, coma and death. Nevertheless its hydrochloride 


1 Treupel and Hinsberg, Arch. exp. Path. Pharm., 33, 216 (1894). 
2 Spiegel and Sabbath, Ber., 34, 1936 (1901). 

3 Faust, Arch. exp. Path. Pharm., 51, 262 (1904). 

4 Dubois and Vignon, Compt. rend., 107, 533 (1888), 


92 ORGANIC COMPOUNDS 


under the trade name of Lenthin is recommended as an 
antidiarrheal even for children.! There is a still stronger 
action observed for the para compound, which causes 
violent inflammations of the internal mucous membranes 
and’ cramp paroxyms. The former effect, however, is 
attributed by Erdmann and Vahlen? to quinonediimine, 


CH=CH 
HN=CC C=NH 
CH=CH: 


which is a first product of oxidation. Quinone imides, 
according to Brissemoret,’ also have a purgative effect 
consequent upon the stimulation of intestinal secretion. 
The ortho compound has also a remarkably great toxicity. 

Toluylenediamines (or diamido toluenes) have a still 
‘more powerful action on the blood, producing icterus 
and hematuria.* 

The blood corpuscles are also peculiarly affected by 
benzidine, NH2—CgH4—CgHs—NHe2. In vitro this sub- 
stance causes the formation of methemoglobin, although 
in the organism it is somewhat less active in this direc- 
tion. In the dog, but not in the rabbit, it causes nausea, 
vomiting and motor unrest, and in all animals it causes 
the appearance of considerable sugar in the urine.° 

An interesting consideration is the influence of hydro- 
genization upon the physiological activity of the aromatic | 
amines.© Thus the two naphthyl-amines produce a 
paralysis of the central nervous system in animals, the 


1 Boye, Zentr. inn. Med., 1905, 113. 

2 Erdmann and Vahlen, Arch. exp. Path. Pharm., 58, 401 (1905). 

3 Brissemoret, Soc. biol., 62, 657 (1907). 

4Stadelmann, Arch. exp. Path. Pharm., 14, 231 (1881); 16, 
118 (1883); 238, 427 (1887). 

5 Adler, Arch. exp. Path. Pharm., 58, 167 (1908). 

6 Stern, Virchow’s Arch., 115, 14; 117, 418 (1889). 


NITROGEN COMPOUNDS 93 


a compound acting more strongly than the 6 compound. 
The latter body causes also a slight contraction of the 
pupil of the eye. Of the two tetrahydro-6-naphthyla- 
mines, 


I II 
CH, CH CH CH, 
HC \/ \C-NHe HON \CH-NHs 
i | 
HC. CH HO. che 
CH, CH CH CH, 


the body (1) which is hydrogenized on the non-substi- 
tuted ring is inactive, and the other compound (II) which 
is hydrogenized in the ring which bears the amino group 
is quite active, causing strong rise in temperature, cramp 
phenomena, and dilatation of the pupil (mydriasis). 
The effect of the compound is considerably increased by 
the introduction of an ethyl group in the amino group, 
‘but a methyl group in this position is without appreciable 
influence. 

If a second amino proup: i is introduced into the non- 
-hydrogenized ring of the first compound (I), we have the 
aromatic alicyclic tetrahydro naphthalene diamine, a 
strongly toxic compound which, however, does not dilate 
the pupil. » 

The influence of hydrogenization upon physiological 
action which we see here, may be also observed in a marked 
degree in the cyclic bases. 


Il Ill 
CH CHe 

Hc’ \cH H.C’ NCH» a ane 

Hol Jc HCL JCH. Woe 


N NH NH 


94 ORGANIC COMPOUNDS 


Pyridine (I) shows, to be sure, some effect upon the sen- 
sory apparatus, the respiration and heart action; but it 
may be considered as being comparatively non-poison- 
ous. Piperidine (II), however, has a very essentially 
stronger action. This acts in warm-blooded animals 
as a cramp-producing poison, which considerably increases 
the blood pressure through contraction of the blood 
vessels, and finally causes paralysis of both central and 
peripheral nerves. Pyrrole (III) is itself a poison, caus- 
ing a central nervous paralysis.2, The greater action of 
this compound compared with pyridine is probably due 
to the reactive imino group. But the effect increases in 
pyrroline (IV) and is still greater in pyrrolidine (V). 
This latter compound, | 


IV ie VI 
HC—CH H»C—CHe H»C—CH2 


tee ae Le] 
H.C CH, H2C CH2, . HxC CH» 
aes 


aoe: 
Sor 


is qualitatively like piperidine, as is also the higher ring 
homologue cyclohexamethylenamine (VI). Quantita- 
tively, however, the effect is not the same. It increases 
from pyrrolidine to piperidine to hexamethylenamine. ~ 
That is, it increases with the size of the ring, as we have 
already noted in the case of the cyclic ketones. As 
further example of this general principle, we may also 
cite the isoximes pyrrolidone (VII), piperidone (VIII), 


1 Brunton and Tunicliffe, J. Physiol., 17, 292. 
2 Ginzberg, Dissertation, Kénigsberg, 1880; cf. Pighini, Arch. 
fisiol., 3, Vol. I (1906). 


NITROGEN COMPOUNDS 95 


cyclohexanoneisoxime (IX) where the order of activity 
is the same as the order of the compounds given. 


vit: VII IX 
Hae, CH, ae, 
Hc co. BAY WS oe ea, 


A Og bo 
NH HO. AO AG «CO 
NH ye 


NH 


Likewise the toxicity increases from quinoline (X) to 
tetrahydroquinoline (XI) to decahydroquinoline (XII).! 


x : Se 
CH CH * CH CH: 
HC & \CH HC ad CH» 
CH N CH NH 
XII XII 
CH: CHe CH CH 
HC c CH, HC? \” \CH 
|| 
Hcl SR cus HCL “A. JN 
GH. NH CH CH 


The same statement holds also in the case of isoquinoline 
XIII and its hydrogenized bodies as well as with their 
homologues and derivatives, among which we shall find 
some of the alkaloids which will receive a special considera- 
tion later. 3 


1 Heinz, Virchow’s Arch., 122, 116 (1890). 


a ORGANIC COMPOUNDS 


As one further example we may mention that the toxic 
effect of dihydroindole (Indoline) is greater than that of 
Indole.! 


Ammonium Bases 


There is a fundamental difference between the com-_ 
pounds of trivalent nitrogen and those of pentavalent 
nitrogen, in other words between those with free valences- 
and those with saturated valences.2 In the case of the 
latter (with pentavalent nitrogen) there is observed quite 
generally a physiological phenomenon consisting of a 
paralysis of the motor end-plates. 

This action is called the curare effect, from the name of 
the poison whose administration was observed to. be 
followed by this action. The intensity of this effect 
diminishes with increasing molecular weight of the com- 
pound. It depends also, of course, upon the structure 
of the compound and the spacial grouping of the radicles 
combined with the nitrogen.? 

Accordingly we find in ammonium bases which result 
from the alkylation of tertiary bases the same special 
physiological properties which belong to these tertiary 
bases; but they are very much weakened in the derived 
bodies. Now then, if this weakening of action takes 
place upon the undesirable effects more than upon the 
desirable therapeutic effects, then we can proceed with 
alkylation. The result is that from alkaloids, for example, 
which though powerful and effective, are of doubtful - 
value, because of injurious side-effects, we may thus: 
obtain valuable and useful derivatives. A case in point 


1 Cuttitta, Bioch. Zentr., 7, 349 (1908). 
* Cf. Spiegel, Z. anorg. Chem., 19, 365 (1902). 
3 Hildebrandt, Arch. exp. Path. Pharm., 53, 76 (1905). 


NITROGEN COMPOUNDS 97 


is that of the methyl atropinium salts. Frequently, 
also, it is a fact that the addition products possess new 
properties. 

The curare effect has been observed for the platinum, 
cobalt, rhodium and chromium ammonia compounds,! 
which argues that in these compounds the ammonia 
is held, as we have assumed, by means of neutral valences. 
Furthermore this same effect occurs in the analogues of 
the ammonium bases, that is in the phosphonium, arso- 
nium and stibonium bases. 

We must admit, it is true, that this curare effect is not 
unconditionally dependent upon the ammonium consti- 
tution. To a lesser degree it is also found in some 
secondary bases (piperidine, coniine, methyl aniline, 
guanidine) and also in nitrogen-free substances of the 
camphor group—in fact in camphor itself. The extent 
to which this effect is favored by the ammonium consti- 
tution, however, has been shown by the investigation of 
Boehm ® on the curare alkaloids. 

He found in this arrow poison, besides the quaternary 
base Curarine, a tertiary base Curine. Each of these 
alkaloids is capable of producing the characteristic effect; 
but the ammonium base Curarine is 226 times as power- 
ful as Curine. This latter alkaloid can be converted by 
methylation into the former. 

Besides the curare effect, there is observed in a series 
of ammonium bases, another action which was first 
observed for natural Muscarine (1), and is therefore 
called the muscarine effect. This consists of the arrest 


1 Hofmeister, Arch. exp. Path. Pharm., 16, 393 (1883) and 
Bock, ibid., 52, 1, 30 (1905). 

2 Fiihner, Ibid., 50, 1 (1903). 

3 Boehm, ibid., 35, 20 (1895), also Arch. Pharm., 235, 660 
(1897). 


98 ORGANIC COMPOUNDS 


of the heart in diastole in consequence of the excitation 
of the inhibitory nervous apparatus. 


I 
ean /CHs—CH (OH): 
3) 3— \ou 


This effect is already exhibited by tetramethyl ammonium 
chloride and still more by tetramethylammoniumtri- 
iodide ! further by iso-amyltrimethyl ammonium chloride 
(If) and by valeryltrimethyl ammonium chloride (IIT).? 


II Ii 
___ /CH2—CH2—CH (CHs)2 ___ LsHe0 
(CH) =NC (CH)=NC 


According to Waller and Sowton the effect upon the 
heart is to be observed in the action of the other bases, 
which are closely related to Muscarine such as Choline 
(IV), Neurine (V) and Betaine (VI). Choline and betaine 
are much less poisonous than Neurine and muscarine. 


It is presumable that stereo conditions in muscarine also 
have important bearing upon its action, because the 
1 Jacobi and Hagenberg, Arch. exp. Path. Pharm., 48, 48 (1902). 


2 Schmiedeberg and Harnack, Arch. exp. Path. Pharm., 6, 110 
(1877). 


NITROGEN COMPOUNDS 99 


choline muscarine obtained by Schmiedeberg from 
choline by oxidation! is physiologically different from 
the natural muscarine.? Both are toxic; but the mus- 
carine from choline causes paralysis of the intermuscular 
nerve terminations and myosis in the pupils of the eyes 
of birds, while the natural Muscarine produces neither 
of these effects. Honda states that the muscarine of 
toadstools has the same action as the muscarine from 
choline. Likewise anhydromuscarine (VII), obtained 
by Berlinerblau* and isomuscarine (VIII) °* differ from 
muscarine in having no action on the frog’s heart or on 
the pupil of the eye. 


_VII VIII 
/LH2—CHO CHOH—CH.OH 
(CHs)s=NC (CH) s=NC 
NOH OH 


A lengthening of the side chain in the derivatives of 
neurine and muscarine diminishes their toxicity. In 
the same way we find in comparing tetraethylammonium 
iodide with the tetramethyl compound that the higher 
homologue possesses the curare effect of the lower body 
but not its muscarine effect.6 The corresponding tri- 
iodide is lacking in both effects.’ But in the case of 
choline, we find that the introduction of’the ethyl group 


1Schmiedeberg and Harnack, Arch. exp. Path. Pharm., 6, 110 
(1877). 

2 Waller and Sowton, Proc. Roy. Soc., 72, 320 (1903). 

3 Honda, Arch. exp. Path. Pharm., 65, 444 (1911). 

4 Berlinerblau, Ber., 17, 1139 (1884); E. Fischer, ibid., 26, 
464 (1893); Nothnagel, ibid., 26, 801 (1893). 

5H. Meyer s. Schmidt, Ann. Chem., 337, 37 (1904). 

6 Jordan, Arch. exp. Path. Pharm., 8, 15 (1877). 

7 Jacobi and Hagenberg, l.c. 


100 ORGANIC COMPOUNDS 


into the hydroxyl causes a strong increase in the toxic 
effect. 


Cyclic Bases and Alkaloids 


Pyridine, as we have already mentioned, has only 
slight effects upon the sensory nerves or upon the respira- 
tion and heart action. It undergoes a special treatment 
in the organism, due probably to the fact that it does not 
combine with either glucuronic acid or sulphuric acid 
after oxidation. It is converted into the methyl ammo- 
nium base, HO-CHsNC3H;.2 Its activity is increased 
by the addition of aliphatic side chains, especially alkyl 
groups, and its effect upon the sensory nerves particularly 
is thus augmented3 In the series pyridine, picoline, 
lutidine, collidine and parvoline there is an increasing 
degree of action which is manifested by an intoxicant 
effect and an increase in the respiration and pulse fre- 
quency. 

The same condition holds true for the derivatives of 
piperidine C5HiiN. Piperidine itself causes a strong 
increase in blood pressure, has a noticeable action on the 
motor end-plates, that is, an incipient curare effect, and 
also has an effect upon the heart action. Pipecoline 
(a-methyl piperidine) has a complete curare effect with- 
out arresting the heart action. The same thing is true of 
a-ethyl piperidine and a-propylpiperidine but in a decreas- 
ing degree. But the real toxic effect of the compounds 
which results in a paralysis of the central nervous system 
and subsequent paralysis of the motor nerve terminals 
rises from piperidine to pipecoline to ethyl piperidine to 

1H. Meyer s. Schmidt, Lc. 

2His, Arch. exp. Path. Pharm., 22, 253 (1887); Cohn, Z. 


physiol. Chem., 18. 
3 Kendrick and Dewar, Proc. Roy. Soc., 22, 432. 


NITROGEN COMPOUNDS ;::">,:,40L 


coniine in a geometrical progression 1:2:4:8. If the 
alkylation is continued very far the ratio is increased. 
If we replace by successive alkyl radicals the hydrogen 
of the y carbon atom in Lupetidine, 


H oS 
= CH, 
H,C-HC CHCH: 


we find that the toxic effect of the resulting compounds 
increases in a geometric progression for an arithmetic 
progression of the molecular weight. But this is true 
only up as far as the propyl derivative. The isobutyl 
derivative shows a decrease again and the hexyl deriva- 
tive a still further decrease! Moreover, the position 
which the radicle occupies upon the nucleus is not with- . 
out material effect. Thus the lethal dose of 6-propyl 
piperidine is nearly twice as great as that of the a-propyl 
piperidine (Coniine). But the lethal dose of 6-ethyl 
piperidine is twice as great as that of the a-propyl com- 
pound.2. We should note here, that alkylation on the 
nitrogen is very important and generally results in an 
increase in the physiological activity of the compound. 
This increase, also, is greater than that caused by alkyla- 
tion on a carbon atom. Here again, there is a rise in 
the effect up as far as the propyl body and then a decrease 
in the higher homologues. Considering the compounds 
where the alkyl radicles are attached to the nitrogen 

1 Girber, Arch. Physiol., 1890, 401. 

2 Ehrlich and Granger, Ber., 30, 1060 (1897) and Giinther, Ber., 
31, 2141 (1898). 


_ 192; 0... 5. SORGANIC COMPOUNDS 


of piperidine we have the following series of lethal doses 
per kilogram of body weight in the case of a rabbit: 


N-methyl : ethyl : propyl : amyl as 
0.4: 0.1: 0.01 : 0.04 


Derivatives formed by acylation on the nitrogen cause 
cramps that can reach a condition of perfect tetanus, 
as in the case of the formyl derivative.! The presence 
of an hydroxyl group in the side chain seems to weaken 
the physiological effect of the compound. For an ‘ex- 
ample, Conhydrine, 
; CHo 


H2C CHe 


H2C CH -C3H.6 (OH) 
NH 


is qualitatively like coniine, but its action is milder.” 
_If the hydroxyl is in the ring, the substances seem to 
be enabled to act upon the brain; but if such hydroxyls 
are covered by ether formation the compounds will then 
further the excitation of cramps. 

The derivatives of quinoline have in general a less 
toxic effect than the corresponding substituted pyridine 
derivatives. In other words the condensation of a benzol 
ring with the pyridine weakens its action. On the other 
hand the inherent antiseptic action of the benzol which 
we may assume it to have, judging from its oxyderiva- 
tives, is considerably increased by this condensation 
with pyridine. 

Let us now take up a discussion of the individual 
alkaloid groups from the standpoint of constitutional 


1R. and E. Wolffenstein, Ber., 34, 2408 (1901). 
2 Wertheim, Ann. Chem., 100, 337 (1856). 


NITROGEN COMPOUNDS 103 


relationships which seem to be responsible for similarities 
in physiological activities. 


Group of Atropine and Cocaine 


These two alkaloids are closely related in chemical 
constitution. Atropine (III) is derived from tropine (I) 
and Cocaine (IV) is derived from Eegonine (II), which 
is the orthocarboxylic acid of Tropine. 


I TROPINE 











He H 
C C CH, 
| cu 
N—CH; CHOH 
| | 
C C CHe 
Hy H 


II EcGonine 
Ho H 
C C CHCOOH 








| 
N—CH3; GHOH 
: 











HoC H CHo 
Til. ATROPINE 
Hy H 
C— 0 CH, 
| | CH,OH 
N—CH; CH-O CO—CHK 
| : | . CeHs 
CH CHo 





3 
bo 


104 ORGANIC COMPOUNDS 


IV. CocaInE 








Ho» 
C- i CH -COOCH; 
| 
Nie CH-O-CO-CeHs 
| 
o— CH CH, 
Hy» 


In both of these compounds the alcoholic hydroxyl is 
esterified by an aromatic acid, tropic acid, 
CH20H 


CoH; CHK 
COOH 


in the case of atropine and benzoic acid in the case of 
cocaine. In the latter, the hydrogen of the carboxyl 
group of ecgonine is further replaced by the methyl 
group. 

There is a definite physiological relationship which 
corresponds to this chemical relation. Both alkaloids 
act in the same way upon the central nervous system, 
the action being first excitant and then paralyzing. 
They both have from the start a paralytic effect upon the 
endings of certain peripheral nerves. But there is one 
essential difference in this action. While cocaine exercises 
this effect essentially upon the ends of the sensory nerves 
(the result being a local anzesthesia) atropine extends its 
sphere of action to all the organs and nerves upon which 
muscarine has an excitant effect. These are the inhibi- 
tory apparatus of the heart, all glands proper, the motor 
elements in the organs with plain or unstriped muscle 
fibers (intestine) and particularly the organs of adapta- 
tion and accommodation of the eye. 

The pupil of the eye is enlarged (mydriasis) on account, 
of the paralysis of the nervus occulomotorius and con- 


NITROGEN COMPOUNDS 105 


sequent lack of nerve control of the ciliary muscle. 
The result is the impossibility of accommodation for near 
objects. This effect of atropine is a local one, just like 
the effect of cocaine upon the sensory nerve ends. 
When cocaine is applied to mucous membrane, it causes 
a pallor due to a contraction of the blood vessels. Other 
effects that may be mentioned are a foamy degeneration 
of the liver,! a strong rise in temperature,” and the prop- 
erty of increasing the capacity for work, which is the 
reason for the extensive use of cocaine in its native land. 
According to some observers* atropine has a feeble 
but appreciable effect on the sensory nerve endings, 
and cocaine causes a weak but long-continued mydriasis. 
Now then, if we are led to believe that the combined 
ring system which is the foundation of these two alkaloids 
is the secret of their action upon peripheral nerve ends, 
we shall at least have to modify our view to include 
the fact that a suitable substitution in these rings is 
essential to the action. For tropine has no mydriatic 
action, but does have an effect upon the heart. Of the 
tropeines (the organic acid esters of tropine according to 
Ladenburg) those of the aliphatic acids act essentially 
like tropine.© But when an aromatic acid radicle is 
introduced, the heart effect becomes more or less ob- 
scured, and the nerve effect becomes apparent.® In this 
substitution, however, the character of the acid radicle 
is the factor which determines whether this effect shal] 
be manifested as mydriatic or anesthetic. The tro- 


1 Ehrlich, Deut. med. Wochschr., 17, 717 (1891). 

2 Reichert, Zentr. med. Wissensch., 1889, 444. 

3 Mosso, Pfliiger’s Arch., 47,.553 (1890). 

4 Filehne, Berl. klin. Wochschr., 24, 107 (1887). 

® Gottlieb, Arch. exp. Path. Pharm., 37, 128 (1896). 
6 Buchheim, Arch, exp, Path. Pharm., 5, 463 (1876), 


106 ORGANIC COMPOUNDS 


peines of benzoic acid, CeHsCOOH, of cinnamic acid, 
CegHs-CH=CH-COOH, of atropic acid, 


CH 
CoHs CK a 
COOH 


and of salicylic acid, 

OH 

CoH 
COOH 


cause anzsthesia but no, or only slight, mydriasis. The 
benzoyl tropeine has a strong anesthetic action and the 
benzoic acid ester of pseudotropeine (which is a stereo 
isomer of tropeine) is the tropacocaine which is found in 
Java coca leaves. This substance has no mydriatic 
effect, and is less toxic and a more powerful anesthetic 
than cocaine. Only when the tropine is esterified with 
an organic acid with a side chain which contains an 
hydroxyl group do we observe the presence of the charac- 
teristic atropine effect. For example, as the tropeine of 
mandelic acid is still nearer to benzoic acid than is tropic 
acid, so the anesthetic power of homatropine is stronger 
than that of atropine. We have already noted that stereo 
arrangement has a considerable influence in these con- 
siderations. According to the investigations of Cushny ? 
the optical components of atropine (dextro and lxevo 
hyoscyamine) are each selectively preferred by certain 
organs, and together they seem to be responsible for the 
total effect of the racemic isomer. It was found that in 
mydriatic effect the levo hyoscyamine is almost twice as 
effective as atropine and is 12 to 18 times as strong as 
dextro hyoscyamine. 


1 Chadbourne, Brit. Med. J., 1892, 402. 
? Cushny, J. Physiol., Oct., 1903. 


NITROGEN COMPOUNDS 107 


Conversion of atropine into alkyl atropinium salts 
such as Eumydrin results in an equal but more evanescent 
mydriatic effect. It also results in a diminution of the 
other poisonous effects, and is therefore advantageous 
for therapeutic use. 

The atropine action remains practically unchanged 
when the alcoholic hydroxyl of the tropic acid is replaced 
by chlorine; but the same substitution by bromine di- 
minishes the effect much more.! 

Eecgonine has no anesthetic effect and benzoyl ecgo- 
nine and ecgonine methylester show only slight indica- 
tions of a cocaine effect.” 

Now one might be led to believe that the effect is 
dependent upon simply the closing up of both the car- 
boxyl and the hydroxyl groups at the same time. But 
this is not a tenable theory, for the esters of anhydro- 
ecgonine (V) are also without effect.3 


V. ANHYDROECGONINE ESTER 








H 

H2C 4 CHCOOR 
oH bs 

H2C bi to 


So we must conclude that this closing up of the carboxyl 
and alcoholic hydroxyl must be accomplished by certain 
groups. For the carboxyl, in general any alkyl radicle 
will suffice. Whether methyl, ethyl, propyl, isopropyl 


1 Lewin and Guillery, Die Wirkungen von Arzneimitteln und 
Giften auf das Auge, Berlin, 1905, p. 204 ff. 

2 Stockmann, Pharm. J. Trans., 16, 897 (1888). 

’ Kinhorn and Konek de Norwall, Ann. Chem., 280, 96 (1894). 


108 ORGANIC COMPOUNDS 


or isobutyl is used the effect is the same.! In the case of 
the hydroxyl group, however, the benzoyl radicle seems 
to be rather essential and unique in its influence. With 
all other acids, the esters obtained have at most only a 
weak anesthetic effect.2 The mandelic acid ester is 
essentially mydriatic like that of tropine. Therefore 
we may say that alkylation removes the disturbing 
influence of the carboxyl group when it is on the carbon 
atom next to the benzoylated hydroxyl group; but. it 
does not do so when it takes place on the same carbon 
atom that carries the hydroxyl. For example, a-ecgo- 
nine (VII) was prepared by Willstatter * from tropinone 








(VI). 
VI. TROPINONE 
CHo CH CHe 
rae 
N—CH3 CO 
| 
HC CH. he 





VII. a-ECGONINE 








CH CH CH» 
| OH 
N—CHs Wa 
| | \COOH 
CH CH CH 


Now if the carboxyl of this compound is methylated 
and the hydroxyl is benzoylated the resulting com- 


1 Falck s. Merck, Ber., 18, 2955 (1885); Novy, Am. Chem. 


J., 10, 147 (1888). 


2 Liebrich and Liebermann, Ber., 21, 2344 (1888); Ehrlich, 
Deut. med. Wochschr., 17, 717 (1891). 
$ Willstatter, Ber., 29, 2216 (1896). 


NITROGEN COMPOUNDS 109 


pound has no anesthetic effect. But we shall see that 
when the nucleus has a somewhat different structure 
this combination may also be active. 

Dextro cocaine has a more intense but more evanescent 
action than the natural levorotary base.! 

The methyl group of the nitrogen bridge seems to be 
without significance for the anesthetic action, since 
Norcocaine (the methyl ester of benzoyl Norecgonine, 
(VIII) possesses this action to the same degree as cocaine 
but has a stronger toxic effect.? 


NORCOCAINE 


CHo C CHCOOH 


| | 
N—H  CHOH 





CHye CH CHe 





A further attachment of methyl iodide causes a loss of 
the anesthetic effect. The effect upon the liver which is 
constantly observed in the cocaine derivatives is also 
absent.? 

The same result is accomplished if an amino group is 
introduced in the meta position in the benzoyl group of 
cocaine. Also, the benzol-sulpho derivatives of this 
amine and of the urea are without effect upon the liver. 
But as soon as the amino group is substituted by acid 
radicles the liver effect is again observed. The acetyl- 


1 Poullson, Arch. exp. Path. Pharm., 27, 301 (1890); Ehrlich, 
loc. cit. 

2 Poullson, loc. cit. 

* Fhriich, loc. cit, 


110 , ORGANIC COMPOUNDS 


amino and benzoylamino cocaine possess no anzsthetic: 
effect; but the corresponding urethane has a greater 
action in this respect, than cocaine itself. Considering 
for a moment the effect of the other substitutions in the 
cocaine molecule we find that halogen and nitro groups 
decrease the anesthetic action without altering the liver 
effect. 

The oxy-cocaines are intermediate in physiological 
action between the nitro and the amino compounds. The 
hydrochloride of dextro-cocaine azodimethylaniline causes 
at most faint traces of anesthesia, while the hydrochloride 
of dextro cocaine-azo-a-naphthylamine causes a distinct 
even if only slight anesthesia. Neither of these: com- 
pounds have the characteristic liver effect.! 

We may say, then, that there is a special significance 
in the henzoyl group. As this was also observed in a 
whole series of benzoyl derivatives of other alkaloids, 
Filehne ? was led to consider this group as directly respon- 
sible for the anesthesia action. But we have seen 
instances where this action is entirely lacking either in 
consequence of a disturbing group (as the carboxyl group 
in benzoyl ecgonine) or in consequence of an unfavorable 
structure, even though that structure differs only slightly 
from that of cocaine (as in the methyl ester of benzoyl 
norecgonine). Further experiences show that although 
the benzoyl group favors this anesthetic activity, it is 
not absolutely essential? We may say then, that the 
- benzoyl group in itself is not directly responsible for this 
action; but that rather the effect is brought about by a 
structure of the nucleus which makes the power of the 
benzoyl group available. A comparison with the sub- 

1 Ehrlich and Einhorn, Ber., 27, 1870 (1894). 


2 Filehne, Berl. klin. Wochschr., 24, 107 (1887). 
8 Ehrlich and Einhorn, loc. cit. 


NITROGEN COMPOUNDS 111 


stances which are mydriatically active forces us to believe 
that the capacity for paralyzing the peripheral nerve 
endings is inherent in the nitrogen-containing nucleus, 
and that the acid radicle acts, we may say as a selective 
anchor which attaches the action to definite nerve end- 
ings. Thus, in the case of the benzoyl group, the sensory 
nerves are the seat of the attachment. In other words, 
in this specific case, the benzoyl group will furnish the 
hold upon the nerves, and whether anesthesia will result 
or not, must depend upon the nitrogen-bearing nucleus 
that is attached to the benzoyl group. 

The fact that the benzoyl group seems to have this 
selective action is responsible for the interest that was 
aroused in the benzoyl derivatives whose structure is 
somewhat near that of tropine. These compounds were 
experimented upon to the neglect of other derivatives of 
ecgonine and tropine. Two bodies which received such 
attention are triacetone alkamine and vinyl-diacetone 
alkamine. Two derivatives of these substances have 
proved to have an anesthetic action very similar to that 
of cocaine. These are Eucaine (benzoyl triacetone alka- 
mine carboxylic acid methyl ester) (1) and Eucaine B 
(benzoyl vinyl diacetone alkamine or 2-6-6 trimethyl 
4-benzoxypiperidine) (II). In this case, as in the cocaine 
series, it appears that the elimination of the methylated 
carboxyl! group is of little importance. That the removal 
of the methyl group attached to the nitrogen does not 
impair the effect is most certainly established by the fact 
that the norcocaines are as active as the cocaines. Other 
relationships between the two series were established by 
Vinci.t Among other points it was found that in this - 
case also only one of the stereometric isomers is active. 


Vinci, Virchow’s Arch., 145, 78 (1896); 149, 217 (1897); 154, 
549 (1898). 


112 ORGANIC COMPOUNDS 


I. EucAINnE 














CH3 
| 
CH3 C CHe 
| | ,COOCH3 
N—H Og 
| | ‘O-CO-CeHs 
CH3 C —CHe 
| 
CH3 
II. Euvcarne (B) 
ie 
CH; C CHoe 
| | 
N—H CHOCOC,.Hs 
| | 
CH3 CH CH» 


The work of Einhorn and Heinz! resulted in a great 
simplification in the complex to be benzoylated. For 
they discovered that it was not necessary, as formerly 
supposed, and as in the case in the cocaines, that the 
nitrogen atom shall belong to a ring system. 

In fact they found that nearly all amino-oxy-benzoic 
acid esters have a local anesthetic action. Representa- 
tives of this group are Orthoform (I), which is the methyl 
ester of para-amino-meta-oxybenzoic acid, and Ortho- 
form new (II), which is meta-amino-para-oxybenzoic acid 
methyl ester. These compounds are difficultly soluble 
powders and are useful only for reacting on exposed nerve 
ends. Such a use is found in cases of burns. The soluble 
salts react too strongly acid and consequently cause an 
excessive irritation of the tissues. It was expected that 


1 Kinhorn and Heinz, Miinch. med. Wochschr., 44, 931 (1897). 


NITROGEN COMPOUNDS 113 


this disadvantage could be overcome by using glycocoll 
derivatives. Nirvanin (III), for example, is the methyl 
ester of di-ethyl-amino-acetyl-para-amino-ortho-oxy-ben- 
zoic acid, and this substance has found practical applica- 
tion.! 


Il. OrTHOFORM EH Ber See NEW 
NHo2 
| 
OF —NH, 
COOCH3 nee. 
III. Nrrvanin IV. ANASTHESIN 


NH-CO-CH2-N(C2Hs5)2 NH» 
| 


OH 


| | 


It was afterwards determined, however, that the 
hydroxyl group is not a necessary requisite for the 
anesthetic action of such compounds. Rissert recom- 
mended the use of the ethyl ester of para-amino-benzoic 
acid (IV), which was marketed under the name Anzs- 
thesin.2 A more recent member of this group is Cyclo- 
form, which is the isobutyl ester of para-amino-benzoic 
acid, NHs—CgH4—COOCu4Hg, investigated by Impens.? 

1 Einhorn and Heinz, Miinch. med. Wochschr., 45, 1554 (1898). 


2 Pharm. Ztg., 47, 356 (1902). 
3 Therap. Gegenw., 51, 348. 


114 ORGANIC COMPOUNDS 


This investigator states that the amyl and the benzoyl 
esters have an even greater effect. This is a good ex- 
ample of increase of action with increase of carbon con- 
tent of the esterifying alkyl group. 

The trouble with these last-named compounds, however, 
is their slight solubility, which renders their practical 
application as analgesics very slight. Even cycloform is 
rather difficultly soluble in water, being only .014 to .022 
per cent at 10° to 22° C. But these solutions have an 
action about as strong as saturated solutions of the propyl 
or ethyl esters, although these contain .03 to .04 per cent 
and .08 per cent respectively. We may in fact find an 
advantage in cycloform over the lower homologues in 
that its solubility results in a correspondingly lower 
resorption capacity. This is an advantage because the 
amino-benzoic acids, just like aniline, cause methzemo- 
globinuria. These compounds in contradistinction to 
the amino-oxy benzoic acid esters, do not in vitro convert 
the blood-coloring matter to methemoglobin. These 
amino-benzoic acid esters are, as a consequence of their 
slight solubility, used almost exclusively externally. 
Subcutine ! is a similar body and is capable of steriliza- 
tion without decomposition; but has not met with a 
very favorable reception. This is a para-phenolsulphonic 
acid salt. The propyl ester of this compound is better 
still, and is used under the name of Propesine.? 

We must remark, however, that none of these 
compounds containing the nitrogen atom on the benzol 
ring has been generally recognized as a wholly satis- 
factory substitute for cocaine. Besides other special 
disadvantages they seem to lack the power of deep pene- 
tration which that substance has. Much better results 


1 Pharm. Ztg., 48, 405 (1903). 
2 Stiirmer and Luders, Deut. med. Wochschr., 34, 2310 (1908). 


NITROGEN COMPOUNDS 115 


were obtained when the position of the nitrogen atom 
was shifted to the alcoholic group. A series of such com- 
pounds which possessed a strong anesthetic effect, was 
prepared by Fourneau.! Of this series the member which 
has proved to be most useful in practice is Stovaine. This 
is the benzoic acid ester of di-methyl-amino-dimethyl- 
ethyl-carbinol (V). The Farbenfabriken vorm. Friedr. 
Bayer u. Co. prepared and introduced another compound 
which they called Alypin (VI) by the introduction of a 
dimethyl-amino group on the second methyl group of 
stovaine.? 

This naturally acts very much like stovaine; but it 
has the advantage that its salts have a neutral reaction. 
A third body in this group was introduced by the Farb- 
werke Meister, Lucius u. Bruening, Hochst a. Main, under 
the name of Novocaine. This is a diethyl-amino deriva- 
tive of their anesthesin, and consequently is para-amino- 
benzoic acid diethyl-amino-ethyl ester or para-amino- 
benzoyl-diethyl-amino ethanol (VIT)3 


V. STOVAINE 
H3C 


(CH3)2N -H2C—C—O-CO-CegHs5 
CoHs5 


VI. ALYPINE 


(CH3)oN - AoC. 
C—O -CO-CeHs 


(CHs)9N-H207 | 
CoHs 


VII. NovocaInE 
(CoHs)2N -CH2-CH2—O -COCgH4—N He 


1 Fourneau, Compt. rend., 188, 766 (1904). 
2Impens, Deut. med. Wochschr., 31, 1154 (1905). 
8 Braun, Deut. med. Wochschr., 31, 1667 (1905). 


116 ORGANIC COMPOUNDS 


Although the investigations upon these three sub- 
stances, particularly on their comparative value, cannot 
be said to be concluded, nevertheless we can say that they 
all stand very near cocaine and the eucaines as far as the 
manner of their anesthetic action is concerned, and 
moreover they have the advantage of being less toxic. 
On the other hand they lack one of the advantages of 
cocaine, which is often desirable, and that is the power 
of contracting the blood vessels. In fact stovaine and 
alypine have the opposite effect, causing a dilation of the 
blood vessels. 

This brings us to a substance which comes to the rescue 
in this condition, a substance which is also related in 
constitution and has in itself a slight anzsthetic action, 
although its pre-eminent powerful effect is vasocontrac- 
tile. This substance is Adrenaline.! 


ADRENALINE 
HO —CH(OH)—CH2—N H—(CHs3) 
HO 


According to Fourneau? the simplest analogue of 
cocaine is obtained from chloroxyisobutyric acid, 


HC 
»>c—0H 
CHC” | 
COOH 


and has the formula 
O-.CO-.C.Hs 


ae 
os 
(CH3)2NH2C COOCHs3 


1 Zeigan, Therap. Monatsh., April, 1904. 
2 Fourneau, J. pharm. chim., (6) 27, 513 (1908). 


NITROGEN COMPOUNDS 117 


It differs from stovaine by having a carboxyl group 
instead of an ethyl group. As a matter of fact it is really 
more comparable with methyl-benzoyl-a-ecgonine than 
with cocaine. Nevertheless it possesses a strong anss- 
thetic power (compare also eucaine). It cannot be used 
in practice because the fundamental basic character of 
the substance is so weak that its salts have an acid 
reaction. Fourneau also says that for a practically use- 
ful cocaine substitute the compound must have at least 
two carbon atoms between the two ester groups. 

A very decided anesthetic effect is shown by the alka- 
loid. Yohimbine ! although it contains no benzoyl group. 
Yohimbine does not have a mydriatic action, but does 
dilate the blood vessels. An anzesthetic effect is found, 
also, in the glucosides of the digitalis group. These 
substances cause at the same time a contraction of the 
pupil and more or less hyperemia.” Anilides have to a 
slight degree an anesthetic action as also have the 
ordinary phenetidine derivatives. The action is, however, 
increased, by the addition of a second basic complex to 
the amino group, as for example in Holocaine, which is 
para-diethoxy-diphenyl-ethanyl-amidine,? 
fn -CgH4-OC2H5 
} CH: Ck 

NH -CegH4-OCoHs 


or in the givGapienyl ae . 


Nak 
NH-CgH,OR 


1 Arnold and Behrens, Chem. Ztg., 25, 1083 (1901). Magnani, 
Miinch. med. Wochschr., 50, No. 28 (1903); Loewy and eT 
Miinch. med. Wochschr., 50, No. 15 (1903). 

2 Korizki, Dimsartation, Petersburg, 1906. 

3 Tauber, Therap. Monatsh., April, 1897. 

4 Trolldenier, Therap, Monatsh., 1899, 36. 


118 ORGANIC COMPOUNDS 


Finally we may mention that this anzsthetic action is 
also found in phenols and phenol ethers with at least 
one free hydroxyl, in a-aminopyridine, tri-methyl- 
ethylene, etc.! 


Opium Alkaloids and Relatives. 


The most important substance in opium is morphine 
(I). This is a phenanthrene derivative, as are also 
codeine (I1) and thebaine (III). 


I. MorpHINE II. CopEINE 











H | | CHe a 
iA). A Ne No” \ H 
cH,HO CH; ie ie 
4 C He ei 2 
LHe CHe 
I. MorpPHINE II. CopEINE 
HO CH;30 
DION oO EION 
Ill. THEBAINE 
CH30 
C,7H,;50N 
CH30 


1 Frankel, Arzneimittelsynthese, 2d Ed., p. 380. 


NITROGEN COMPOUNDS 119 


Morphine and of course codeine, which is methyl 
morphine, are derived from hexahydrophenanthrene, 
while thebaine is derived from tetrahydrophenanthrene. 
The physiological effect of morphine is somewhat compli- 
cated. In the first place it diminishes and finally stops 
the functioning of the cerebrum, particularly the power of 
sensation. This is the cause of the most potent and 
important. results of the administration of morphine, 
which are a deadening of pain, hypnosis, euphoria and 
narcosis. After larger doses the paralysis extends to 
the voluntary movements and to the reflex movements 
which depend upon pain production for excitation and 
which are also finally completely suppressed. In some 
kinds of animals morphine acts like strychnine in causing 
an increase in the sensitiveness of reflex actions, which are 
controlled by sense excitation. This effect is much more 
pronounced in the case of codeine, and is entirely pre- 
eminent in thebaine, which should be placed, as far as 
physiological action is concerned, in the strychnine group. 

Morphine is attracted to the brain and is here largely 
destroyed. The extent of the attraction and destruction 
by the brain substance is, moreover, commensurate with 
the habituation or tolerance which results from continued 
use.! 

First of all, it is of interest to investigate the extent of 
the réle of the phenanthrene nucleus in this effect. It 
is true that Overton has stated that phenanthrene itself 
acts as a narcotic on tadpoles; but with warm-blooded 
animals it has no such action. On the other hand, it 
undoubtedly does have a tetanic effect. This is also 
true of the phenanthrols, the carboxylic acid, and 
even of the sulphoacid. 4-methoxy-phenanthrene-9-car-_ 
boxylic acid acts like phenanthrene carboxylic acid. A 

1 Cloetta, Arch. exp. Path. Pharm., 50, 453 (1903). 


. 


120 ORGANIC COMPOUNDS 


further addition of alkyl and acid groups upon the 
hydroxyl diminishes very considerably the cramp produc- 
ing action and the general toxic effect. None of these 
preparations, however, possesses any narcotic action.! 

The action of phenanthrene quinone derivatives, is 
somewhat different. Phenanthrene quinone-3-sulphonic 
acid has no cramp effect, but does cause pronounced 
methemoglobinuria,? 2-brom-phenanthrene quinone sul- 
pho acid causes strong poison phenomena and degenera- 
tion of the organs, and is said to act, when introduced 
directly into the veins, in a manner similar to morphine, 
in so far as it retards and diminishes the respiration.® 
According to Pschorr* we must also consider as belong- 
ing here the Epiosin of Vahlen® which is methyl- 
diphenylene-imidazol (IV). This substance dulls the 
sensibility for pain, has a slight hypnotic effect, and a 
strong cramp, producing action. Like Schmidt’s com- 
pound, it causes an increase in blood pressure. 


IV. Eprosin 
CH , 

hice aca 

| ) CH 
ae A om 


1 Bergell and Pschorr, Z. physiol. Chem., 38, 17 (1903). 
2 Ibid. 

3 Schmidt, Ber., 37, 3565 (1904). 

4 Pschorr, Ber., 35, 2729 (1902). 

* Arch. exp. Path. Pharm., 47, 368 (1902). 


NITROGEN COMPOUNDS 121 


According to Pschorr the morphine-like effects are not 
caused by action upon the nerves, as in the case of mor- 
phine itself, but by a poisoning of the blood. 

Therefore it seems as if the narcotic effects of morphine 
were dependent upon the addition of a: nitrogen-contain- 
ing ring. In order to cause a stronger action the phenolic 
hydroxyl of the morphine must be free, for it is evident 
that this group functions as a binder of the alkaloid to 
the nerve substance. To be sure, codeine, in which this 
hydroxyl is methylated, does produce in small doses a 
narcotic effect, but it is of much shorter duration and less 
deep than that of morphine. Upon the administration 
of larger doses of codeine, this narcosis is hardly per- 
ceptible, because the tetanic effect becomes of paramount 
importance.! 

The same is true of the action of ethyl morphine 
(Dionine), amyl morphine and benzyl morphine (Pero- 
nine). Similar changes in effect are caused by the intro- 
duction of acid radicles such as acetyl, benzoyl, ete., into 
the phenolic hydroxyl.2 Such compounds, however, 
stand nearer to morphine than do codeine and its homo- 
logues, because in the former compounds the radicles 
which hinder or retard the morphine effect are more 
easily split off. Diacetyl morphine (Heroine) finds a 
considerable practical application. The inorganic acid 
radicles act in a manner similar to the organic acid 
radicles. ‘The more easily the acid radicle can be split 
off, the more nearly the effect approaches that of mor- 
phine. For example, the carbonic esters and the car- 
bonic acid alkyl esters of morphine act very much like 
morphine, according to von Mering. Winternitz? states 


1Stockmann and Dott, Brit. Med. J., 1890, II, 189. 
2Ibid.; v. Mering, Merck’s Jahresber., 1898, 5. 
3 Winternitz, Therap. Monatsh., Sept., 1899. 


122 ORGANIC COMPOUNDS 


that alkylation of morphine weakens the effect upon 
the respiration, but acylation strengthens it very 
materially. 

These derivatives of morphine furnish remarkable 
examples of the fact that it is exceedingly dangerous and 
uncertain to assume that a chemical compound will have 
the same effect upon man that has been observed with 
other warm-blooded animals. For example, codeine is 
much more poisonous for rabbits than is morphine. For 
man, on the contrary, codeine is much less poisonous.! 
For experiments which affect the nervous system it 
appears that the cat is most suitable if the results are to 
be compared to those in man. | 

Of the products which result from tearing down the 
morphine molecule, apomorphine is only a mild narcotic, 
but it has a powerful emetic action, which is to be attrib- 
uted to the free phenolic hydroxyls. The reason for 
attributing it to these groups is that a half alkylation 
leaves only a suggestion of the emetic action, and complete 
alkylation or acylation removes it entirely.? 

On the other hand this specific emetic effect is not de- 
stroyed by conversion into quaternary compounds. | 
For example, the effect is retained in apomorphine brom- 
methylate (Euporphine), but the undesirable’side effects, 
such as action upon the heart, are said to be eliminated? 

The methylated derivative, apocodeine, acts as a 
sedative and purgative.t Dixon® states that it has a 


1Mayor, Therap. Monatsh., May-June, 1903; Vinci, -Arch. 
ital. di Biol., 47, Vol. III (1907). 

2 Michaelis, Klin.-therap. Wochschr., 1904, 660; Kaminer, 
Festschr. f. Salkowski, p. 205. 

3 Schiitze, Berl. klin. Wochschr., 48, 349 (1906). 

4 Guinard, Contribution a l’étude physiologique de l’apocodeine, 
Lyon, 1893. Toy and Combemale, Merck’s Jahresber., 1900, 62. 

5 Dixon, J. Physiol., 30, 98 (1904). 


NITROGEN COMPOUNDS 123 


paralytic action upon the nerve cells, thus causing dila- 
tion of the blood vessels, that it depresses the blood 
pressure, accelerates the heart frequency, and excites 
the automatic movements of the smooth muscles. More- 
over, it increases the reflex action even to convulsions, 
like those caused by strychnine, and nally: it has a 
curare effect. 

The methyl-morphimethines 

/PH (OH) 
CHs0-CioHlsC CH. O.CH2-CH»-N(CHs)2 
H—CH 

act neither as relievers of pain, nor as sleep producers. 
They do, however, like morphine, paralyze the respiratory 
center, and unlike it lower the blood pressure. 

Intermediate in effect between morphine and codeine 
stands papaverine (I) } 


I. PAPAVERINE 
A H 


HsCO- A H 


H CH» 
no’/~ H 
H 


-OCH3 
f 


OCHs 


1 Schroeder, Arch. exp. Path. Pharm., 17, 96; Leubuscher, Deut. 
med. Wochschr., 18, 179 (1902). 


6 


124 ORGANIC COMPOUNDS 


Laudanosine, which is the tetrahydro derivative of 
papaverine, but is methylated on the nitrogen! has no 
appreciable narcotic effect, and is in both its action and 
toxicity similar to thebaine.? 

Narcotine (II) is nearer to morphine both chemically 
and physiologically. It has, however, a much weaker 
narcotic effect, which is preceded by a tetanic effect of 
short duration. Hydrastine (III) is very closely related 
chemically to narcotine; but it has no narcotic effect, 
and we must attribute this lack to the presence of a 
methoxyl group. Hydrastine has a toxic effect which is 
manifested by general paralysis and tetanus. 


II.. NARCOTINE 





CH CHe 
T ae A 
O—C C CHa 
HCC | 
O—C C N-CHs 
Mi NZ: 
on 
H3CO ela 2 
C 
\ 
HC C— CO 
a 
) 
OCH3 


The strychnine-like excitant action of hydrastine upon 
the central nervous system is manifested first through the 


1 Pictet and Athanasescu, Ber., 33, 2346 (1900). 
2 Babel, Rev. méd. de la, Suisse rom., 1899, 657. 


NITROGEN COMPOUNDS 


IIl.. HypRASTINE 








CH CHs 
oor oe on, 
HACC 
‘ema eats adie: 
ae 
CH CH 
| 
CH 0 
| 
(: 
\ 


125 


vasomotor nerves, so that small doses cause a contrac- 
tion of the blood vessels and thus an increase in blood 


Considering for a moment the action of some 


IV. HybDRASTININE 


of the deeaunsesiion products of these two alkaloids, 
we find that opianic acid is narcotic through a paralysis 
of the central nervous system in cold-blooded animals, 
but in warm-blooded animals it is without effect. Hydras- 
tinine (IV) is distinguished from the parent body by an 
absence of the tetanic stage and by a detrimental effect 
upon the heart. 


_ 126 ORGANIC COMPOUNDS 


It causes vaso-constriction and thereby a rise in blood 
pressure, and a lowering of the pulse frequency by action 
upon the vessels themselves. Cotarnine (V) has been 
known longer, and its chemical similarity to hydrastinine 
induced the belief that it also, like hydrastinine, might 
possess astringent and styptic properties. 


V. CoTARNINE 
CH. CHz2 


Y 
Oso 8 - cH 
HC : 


| 
O—C| C NH.CH; 
es 
C CHO 


bon, 

The hydrochloride (Stypticine) and later the phthalic 
acid salt (Styptol) were in fact found to have a styptic 
action. But, strange to say, the cause of this action was 
quite different from the cause of the similar action of 
hydrastinine salts. For the stypticine and _ styptol 
cause neither a vaso-contraction nor blood coagulation.’ 
Their styptic effect probably depends upon a slowing of 
the respiration and consequent reduction of arterial blood 
pressure. The action of cotarnine is similar to that of 
the parent substance, narcotine. It causes first an. exci- 
tation of the central nervous system, and then a general 
paralysis.2 It is claimed by Williams? that an intrave- 
nous injection of hydrastis causes a lowering of the blood 
pressure by a reduction of the action of the heart muscles. 

Hydrocotarnine has the typical effect of the codeine 
group.t 

1 Marfori, Arch. ital. di Biol., 1897, Vol. II. 
2 Falk, Therap. Monatsh., 1895, 646 and 1896, 28. 


3 Williams, J. Am. med. assoc., 50, 26 (1908). 
4Stockmann and Dott, Brit, med, J., 1891, 24 Jan. 


NITROGEN COMPOUNDS 127 


Berberine (I) acts like hydrastine, but is more powerful.! 


(1) BERBERINE. 
CH CHOHCH, 


Hof’ Os Ga: 
CH: 
wore, J us Ys 


a cae 





1 
OCH; CH| |\c——o 


C—0——-~-CHe 


The corydalis alkaloids, with the exception of the very 
weakly basic corytuberine, produce in cold-blooded ani- 
mals a morphine-like narcosis. These alkaloids stand 
very near, chemically, to those we have just been discuss- 
ing, as will be seen from the structural formula proposed 
for corydaline (II) by Dobbie and Lauder.? 


II. CoryDALINE 








= 
1 Williams, loc. cit. 
2 Dobbie and Lauder, Journ. Chem. Soc., 81, 145, 157 (1901). 


128 ORGANIC COMPOUNDS 


These corydalis alkaloids can be chemically and also 
pharmacologically divided irto three groups: First, 
the corydaline group (corydaline, corybulbine, iso- 
corybulbine); second, the corycavine group (corycavine 
and corycavamine); third, the bulbocapnine group (bul- 
bocapnine, corydine and corytuberine). Common to 
all three groups is a narcotic effect, an action on the 
heart, consisting of a weakening of its general capacity 
for reaction and injury to the muscle motor apparatus. 
Besides these common effects the alkaloids of the first 
group cause paralysis of the spinal cord, the second 
stimulate the motor centers and the third group resemble 
codeine in action and cause increased reflex excitability.! 


Veronal Group | 


The investigations of E. Fischer and v. Mering on di- 
alkylated acids and their derivatives? are very instruc- 
tive concerning the influence of an accumulation of 
alkyl groups upon a compound, the effect of the size of 
the radicle and the effect of the constitution of the ring 
in the production of narcotic effect. We produce, there- 
fore, an exhaustive table of experiments which were 
made upon dogs. From this table one can observe that 
there is no sleep-producing effect until we come to the 
urea group, and it is decidedly stronger in a cyclical 
arrangement of this group. Furthermore, it is essential 
that there be in the combination a group that contains 
several alkyl radicles rich in carbon. 

These alkyl radicles cause an increase in effect with 
rising carbon content of the radicle up as far as propyl, 
and after that the effect again diminishes. A very strik- 


1 Peters, Arch. exp. Pathol. u. Pharmakol., 51, 130 aiate 
2 Therapie der Gegenwart, 5, 97 (1903). 


129 


NITROGEN COMPOUNDS 





*SSOUTA BOY OO—HN 
pue ssouensea 4YSI[Q | SUIs G°Z Gc‘. | ye urloyuspAYTAYIIC “TT 
"4099 O[QISIA ON | “SUIS G*T HN—00—O="(H*0) 
“SSOUISMOIP pue 
ssouonsea ‘AqQUIeyI00 
-un ‘sInoy [BI9AVs JOT | ‘Ws T c “HN: OO’ HN: 00: HO="H®O)) vornjAyoovyAdoidiq ‘oT 
‘qyooyo uorvdde oN'| "ws T c 
“SSOUIZZIP—yoo}jo 
Joqyje ponul}zuo0. Zuo] 
‘ioy [| Joye doosjg| ‘sud ¢ Gc 
UOT} 
“IxozUl Jo BuUaMIOUDY | “sws Z 8 “HN: 00° HN: 00° HO="*(H*0) Born[AJooRIAUIOIC, “6 
‘SHAILVAINAC VAUQ “OC 
: a FN: 0902 (HO) sec cee) or a 8 
; : A . == (447 oprlurvuoyls oidiq *2, 
Le EHN-OO)=—O—=CHD)|  eprUTEUOTEENTATVICT “9 
"HN: 00° HO="*(°H%0) oprurvzooR[ Ayo, “G 
SUaINY ‘gq 
Pee 
SO | HOOD: ?H%0)0=*(*HO)) 919908-[Aq}0-[AG ou “F 
"U0I}0B ON jlod ‘suis Gg)", HOOO: (HO)O=*(*H%0) plow oexojAypI “¢ 
*(HOOO)=0=(*H%O)) plow oruoyeumypAyyoIq’ *% 
HOOD: HO="(*H%O)| = PHB OeOBTAYIOIC, “T 
Sadly “VY 
“U0T}OV ‘asoq =| 24 Teuayue ‘uOTINIYSUOD “~punodulo9 








JO JU31IOM 











ORGANIC COMPOUNDS 


130 





f rie 





‘SSOUISMOIP JUSISUBIT,| “Wd T G') Oe. | “vom 
: : HN—0O sae 9 -jAuojeuypAdoidyAqyoy “OT 
*yUsTIOAOUI 
jo AQureyiooun: ywoIs 
114s sem otoyy Avp 
SUIMOT[OJ 949 JO UOOU 
-19jje 943 UG ‘ABP 
gjoyM oY} BUTySv] 
‘dass doap ‘iy T JoqJy | “suis ¢ /u N—OO "TI 
"yooyo O "us ; Sk von 
Pat St OO\IN—007 > Mg | “Muoremcqercqony “ST 
HN—OO "HO 
‘U01}0B ON | =‘“SUIZ E 9 OX a eoin,AuoleulAQyouNd “FT 
/HN—OO*7\_/H “ean 
oO ty -[AuoyeuAdoidouopy “ET 
NyN—007~ “HO 
*q00J9 O[qvIooIdde ON | ‘SWId F-¢ 9 4 
OO”D ea oN -[AuojeupAqyeou0yy ‘ZT 
HN—OO Ol 
“uOT}OV -as0C, en, “UOI1}NITSUOD ‘punodurop 

















131 


NITROGEN COMPOUNDS 


(9061) FFL ‘EG “IYOSUSYOO AA “POU “YOUN ‘USYOSOW ‘(906T) LETT ‘2b “Id ‘pou ‘usTM ‘IoIOpUNAA 
‘ATET ‘SO6T ‘MIUIM “PEW ‘Suey “A pue soyos!q “Jouvdoid oind ey} UL peAIesqo 40U Ss] JooMe o1x0} SUOI4S OYL x 





JHN—OOD7~'7. Se "HO 
‘qyooyo quorvdde ON | ‘suid ¢ Gs OO” DP, ne | 
HN—OO HOH’)! vomyAuopeuézueqiq ‘zz 
‘davejs ou ‘ssourzziq, | “suis 7+ ; /H N—OO~\. Vp a 
“qoayje Ou “sIy Z Jo}JY | “WIS | c'L ere a 7 Nae denn "eon 
ae a UyAUTBOSTICT “1S 
‘dosjs Sanoy g ueyy /HN—OO”7~V. / HO 
‘uoryeorxojuT AABOY ‘us T acy OOD PS ‘Bain 
soynulMt Og J0yJV HN—OO H’O} = ~[AuoyeujpAgngosiiq “0z 
, Pvep Surusto0W 
4xou ‘daays axyI[-Yyeop 
Soqy Nurul oT ro4hV ‘SUIS Z 8 Neale oi 
‘soy ae 
QP I9AO Suljsvy doeys "Us [ GZ 00 ; ac (jeuvdoig) 
deep seyNUIU YE 10IJV HN—OO 4H} BornyAuoreupAdoidiq, “6 
am Lyye- 
a $Z Bulysey dooys 8 | 8 ere HN OK HO : ee 
Se eee ema NHN—00% ~ H*9) -Auoyempsdordycyyg “gt 
‘sInoy FZ IdAO 
Suse, desis doop . 
®@ soynUIUL (Eg Joyjy| ‘sus G | | JHN-OO\,. (HO 
anog T ( 22 OO~\. fee ([BU019 A ) 
I9AO 9]} 41] B 104 daa[g ‘us T |) HN—OO “F2O| vointAuoyeuypAyyiq ‘LT 
‘U0l}oV ‘asoqd spe bey ‘uoIqN44SUOD ‘punoduiop 

















ORGANIC COMPOUNDS 


132 


"yyeap 
sinoy Zieyjy ‘does 





HN—O HO 
sot Os. 


‘som 





deap moy , wyy| ‘way L NHN—00%~ MHtO| -ormauopempAqaarq *9z 
( HN— Ley? 
ENS ‘ourpruen3 
NuN—00%" Mito} -[AuoywuryXdoadicy “gz 
‘gooyo ON | ‘sud ¢ pi | 
; z . . H . orys 
HN*OO N sage Fr H°O eopae 
| HOOD” HED) prow oruopempAyyar “4g 
*SBUTYO}IMY 
qyss doeejs ayy 
Sung ‘Yyyvep uy} 
‘sAep z Buljse] doosjs 
doop soynutuUl QZ 104jB HN—O aS ie) 
ie AABOY OO Sot ‘eoin[AUO[BUI 
‘soynulut QT eyV | “WS T 9 (HOSN——00% “HO! -14q70m-N-TAqIAI “ez 
‘UOIOV ‘aso a iia UOIyNIWSUOD ‘punodui0p 

















NITROGEN COMPOUNDS 133 


ing phenomenon is the increase in toxicity upon methyla- 
tion on the nitrogen (23) and upon the introduction of 
sulphur in place of oxygen (26). Contrary to this is the 
replacement of the same oxygen by NH (25) which nulli- 
fies the action. It is easier to understand removal of 
the effect caused by a free carboxyl group (24 as com- 
pared with 9). It would be interesting to determine 
whether esterification of this group would reestablish the 
effect. 

A slight chemical modification of Veronal which has 
given rather surprising physiological results is the so- 
called Luminal of the Farbenfabriken of Elberfeld. One 
of the ethyl groups of veronal is replaced by phenyl, 
giving phenyl-ethyl-barbituric acid: 


CoH, CONE 
Set 
CH” *\co— ay o. 


Although in general the aliphatic radicles are more effect- 
ive in sleep-producing action than aromatic radicles, 
the reverse seems to be true in this case since, 0.2 gm. of 
Luminal is equivalent to 0.5 gm. of Veronal. According 
to Impens, however, this hypnotic action of the aromatic 
radicle can take effect only when there is attached to the 
same carbon atom with it one or two other alkyl groups. 


Quinine and Fever Remedies Deduced from Quinine | 


According to Schmiedeberg! the general character of 
the physiological action of quinine is probably to be inter- 
preted as being a sort of mortification effect for all the 
organs concerned. The functions or the functional 
capacity of the organs, and their nutrition processes are 
at first increased, then lowered, and finally entirely 

1 Schmiedeberg, Grundriss der Pharmakologie, 1902, p. 179. 


134 ORGANIC COMPOUNDS 


destroyed, as in the case of mortification from other 
causes. 

A .5 per cent to 1 per cent solution of quinine imme- 
diately suppresses the movements of all kinds of infusoria. 
A solution of this concentration also stops the amceboid 
movements of the white blood corpuscles of mammals. 

For man and other mammals small doses lessen the 
pulse frequency and increase the blood pressure, while 
larger doses (upward from 1 gm. in the case of man) 
cause a decrease in pulse frequency and also a decrease 
in blood pressure. At the same time there appears a 
weak morphine effect on the sensory brain sphere, which 
is called quinine intoxication. Smaller doses cause also 
at first a rise in the body temperature; but larger doses, 
not sufficient for poisoning effect, of course, have an 
insignificant effect on temperature in a normal invididual, 
-but cause a considerable drop in temperature of a fever 
patient. This action is stronger in antipyrine and the 
salicylic acid group than it is in quinine. But quinine 
is much preferable to these compounds or in fact any 
other substance known at present, as a specific against 
malaria. 

Metabolism as measured by the nitrogen excretion is at 
first increased by quinine and then often considerably 
diminished. In fact it is always largely diminished after 
large doses. Quinine is for the greater part destroyed in 
the organism if ingested in moderately small quantities. 
Giemsa and Schaumann! state that the power of the 
organism in destroying quinine is increased with repeated 
dosage with the substance. Schmitz,? however, was 
unable to confirm this statement. 

1Giemsa and Schaumann, Arch. Schiffs. Tropen hyg., 11, 


Vol. III (1907). 
2Schmitz, Arch. exp. Path. Pharm., 56, 301 (1907). 


NITROGEN COMPOUNDS 135 


The constitution of quinine can be to-day regarded 
with a considerable degree of certainty as being formula 
(I).! The side chain of the para-methoxy-quinoline that 
contains a piperidine ring is designated as the loipone or 
meroquinine part of the formula. Of the accompanying 
alkaloids cinchonine (III) stands very near to quinine, 
since it lacks only the methoxy group in the para position. 
But this very slight chemical difference reduces the effec- 
tiveness of the physiological action tremendously. Cin- 
chonine is more detrimental to the heart, and possesses a 
cramp-excitant effect that is only very slightly apparent 
in quinine. Moreover cinchonine is a much less efficient 
febrifuge, and its specific action against malaria is only 
vaguely apparent, and only after large doses. But it 
seems to be clear that the secret of the action of the 
methoxyl group les in the covered hydroxyl group, 
because the higher alkyl derivatives obtained from cupre- 
ine (II) such as quinethyline, quinpropyline, quinamyline 
have an action still more powerful than that of quinine. 
In other words, the more readily oxidizable is the alkyl 
group which covers the hydroxyl, the more powerful is 


I QUININE 


ne Hsorconen 


CH owt 2 
H3CO- 


N 


N 
1 Compare Rabe, Ber., 40, 3655 (1907); 41, 62 (1908). 


136 ORGANIC COMPOUNDS 


the action of the compound ! on account of the greater 
ease with which it is split down to cupreine. 


II CuprEINE 


H 
cameo: 


2 


CH (OH)-CH i) CHe 
OH pee ee 


W 


N 


III CrncHONINE 
CH 
cay GACH-CH=CH: 


H eRe a tas 


N 


N 


It seems, then, very probable that the slight febrifuge 
effect of cinchonine may not belong to that substance 
itself, but is due to cupreine, which is formed within the 
organism by the hydroxylation of the cinchonine in para 
position. In fact we have many cases analogous to this. 


1Grimaux and Arnaud, Compt. rend., 112, 766, 1364 (1891); 
114, 548, 672 (1892); 118, 1803 (1894). 


NITROGEN COMPOUNDS. 137 


The earliest and most numerous investigations as to 
the connection between the effect of quinine and its con- 
stitution started from the quinoline part which was 
demonstrated to be present. At first there was assumed 
‘to be a_ tetra-hydroquinoline ring. Quinoline itself 
proved to be antiseptic, antizymotic and antipyretic 
in its effect. It was found to be weaker against fever 
than quinine and to be entirely useless against malaria. 
Moreover it caused some detrimental effects such as 
collapse and difficulty in respiration, even with the admin-. 
istration of small quantities. 

A recent quinoline derivative which deserves particular 
mention is Atophan, which is 2 pera quinoline tear: 
boxylic acid. 


eee 


Q re 


This substance has found practical application in acute 
attacks of gout because it causes an extraordinary increase 
in the elimination of uric acid. On account of the 
relation of quinine to quinoline, the derivatives of this 
latter body have been subjected to considerable physi- 
ological examination. Nicolaier and Dohrn? examined 
a series of the quinoline carboxylic acids, particularly in» 
regard to their effect on uric acid excretion. From their 
_results we may say that the 4 position for the carboxylic 


1Donath, Ber., 14, 178 (1881); Biach and Loimann, Virchow’s 
Arch., 86, 456 (1881); Brieger, Z. klin. Med., 4, 296 (1882); v 
Jacksch, Prager med. Wochschr., 1881, No. 28. 

2 Nicolaier and Dohrn, D. Arch. f. klin. Med., 98, 331 (1908). 


138 ORGANIC COMPOUNDS 


group is favorable; but the unsubstituted 4 carboxylic 
acid is without effect, as is also the 2-4 dicarboxylic acid. 
But if an aliphatic or aromatic radicle is introduced in 
the 2 position then the increased uric acid excretion is 
caused. This action is slight for the methyl-substituted 
body, but strong for the phenyl. Given this compound 
(atophan) the effect remains unchanged upon introduc- 
tion of a second phenyl group (in 3 position), of a second 
carboxyl group (in 3 or 8 position), or of a methyl in 6 po- 
sition, and hydroxyl weakens the effect. The exact 
behavior of atophan in the organism is as yet not fully 
understood. Very little of it is excreted unchanged. 
Moreover the increase in uric acid excretion cannot be 
ascribed to an increased nucleine destruction because the 
excretion of total nitrogen, phosphoric acid and sulphur 
is not increased. In fact the action would almost seem 
to indicate that the atophan releases an amount of uric 
acid which has been stored up in the organism, for after 
the discontinuance of the atophan treatment the uric acid 
- excretion falls below the normal. The only other com- 
pound of those examined by Nicolaier and Dohrn which 
showed a similar action was 2-phenyl-3-oxyquinoline-4- 
carboxylic acid. 

Isoquinoline is similar in every respect to quinoline.! 
When hydrogen of the quinoline is substituted by methyl 
groups the effect is weakened, but is qualitatively the 
same. The introduction of methoxyl in the para posi- 
tion in quinoline weakens the antipyretic effect which is 
just the opposite of the action of the same group in the 
relation between cinchonine and quinine.2 A con- 
siderably stronger antipyretic body is para-methoxy- 
tetra-hydroquinoline (Thalline) (I) whose effect, however, 


1Stockmann, J. Physiol., 15, 245 (1894). 
2 Tbid, 


NITROGEN COMPOUNDS 139 


is of short duration. This substance is also injurious to 
the blood and kidneys. 


I. THALLINE 
CHe 


HCO Un 
Te 


This effect is not altered either by the introduction of 
alkyl radicles, nor by the introduction of acid radicles 
in the imino group. A similar condition holds also with 
kairine (II) and kairoline (III) which are both prepara- 
tions which are without a methoxyl group, and are alky- 
lated on the nitrogen. 


IT. Karrine III. Karrouine 
CHo CHo 
Vi Give jp ( i 
aes os Ba. 4 Jor 
i ee OH ee or C2Hs) 


None of these quinoline derivatives approaches the specific 
effect of quinine. 

In the meroquinine residue of the quinine molecule 
the binding of the piperidine nitrogen by the bridge 
containing iydroxyl is of prime importance. If this is 
split off, as in the change from quinine to quinotoxine 
(IV), or in the same way if cinchonine is converted to 
cinchotoxine, these new substances do not behave as 
febrifuges at all, but as a digitoxine-like poison.1 We 


1y. Miller and Rohde, Ber., 38, 3214 (1900), 


140 ORGANIC COMPOUNDS 


are, however, hardly surprised by this toxic effect, when 
we note the presence of two groups of particularly great 
capacity for reaction—the CO and the NH groups. 

The unsaturated side chain of the quinine seems to 
have a definite significance. If hydrogen is added at the 
double binding, the poison effect is hardly changed for 
mammals and infusoria. Hydrochlor-quinine, which is 
formed by addition of HCl, is said to be less poisonous 
for mammals than quinine, although it is more poisonous 
for certain infusoria.! 


IV. QUINOTOXINE 








H3CO 


In order to have a sort of standard test body that 
might stand as near as possible to the object..of attack 
of the specific quinine effect, the malaria parasites, 
Tappeiner? selected the paramecium, and undertook 
experiments upon it. It was found that the order of 
strength in quinine effect is first para-methoxylepidine 
(V), then lepidine (VI), and finally quinoline; but that 
meroquinine (VII) is entirely without such effect. 

1 Hunt, Arch. intern. pharmacodyn, 12, 497 (1904). 


2y. Tappeiner and Grethe, Deut. Arch. klin. Med., 56, 189, 369 
(1896), 


NITROGEN COMPOUNDS 141 


V. PARAMETHOXYLEPIDINE VI. LEePIpDINE 
CH3 CH3 
H,coO—7 \ \ 
| 
\ VW Ne 
N N 


VII. MEROQUININE 
CH—CH,-COOH 


HOC \cH CH=CH, 
ILC CH 
NH 


On the other hand y-phenylquinoline (VIII) is con- 
siderably stronger in action than quinine. 


VIII. y-PHENYLQUINOLINE 
CeHs 


| 
OO 
ae 
N 
We may conclude, then, that the action of quinine upon 
infusoria proceeds from the quinoline ring, and can be 
materially increased by the complex attached to it in the 
7 position, even though this complex be in itself inactive. 
Since the substitution of the benzol ring proved to give 
such an effective compound it was natural that the 
phosphines, the beautifully colored compounds obtained 
from acridine, such as chrysaniline (IX), should be 


tested out. This was done, and they were found ex- 
traordinarily effective. But these substances, as well as 


142 ORGANIC COMPOUNDS 


phenyl-quinoline, do not seem to destroy the malarial 
parasites, but only to paralyze them in a manner similar 
to the constitutionally related methylene blue (X).! 


IX. CHRYSANILINE X. METHYLENE BLUE 


NNHe 


9 Cl 
7. 
J ext GOR 
NXNHo c 4 
| N 


< VA 
N 





The constitution which Knorr first? ascribed to a 
tetra-hydroquinoline derivative was the cause for test- 
ing out the so-called dimethyl-oxy-quinizine (I) with a 
view to finding antipyretic effects, and such an effect 
was found to be very pronounced ? and led to the name 
of this compound, Antipyrine. 


J. ANTIPYRINE 


CH NN.CHe 
HOF .CHs 
H He 

CH CO 


It was only later* that this compound was recognized 


Mannaberg, Arch. klin. Med., 59, 185 (1897). 
2 Knorr, Ber., 17, 546, 2032 (1884). 
8’ Filehne, Z. klin. Med., 7, vol. 6 (1884). 
4 Knorr, Ann. Chem., 2388, 137 (1887). 


NITROGEN COMPOUNDS 143 


as dimethyl-phenyl-pyrazolon (II). Michaelis! affirms 
that the formula (III) can also be ascribed to this body. 











Il. ANTIPYRINE Ill. ANTIPYRINE 
co ‘+ CHg 
| 
/ 2 3 | \ 
CoHs NC CsHs—N >O 
\5 4 Sy 
CO CH C————_C'H 


Antipyrine does not act against malaria, but aside from 
this it is to be preferred over quinine, as it has less undesir- 
able side effects, and it has a specific anti-neuralgic action. 

The alkylation of the nitrogen is of importance. 
Phenyl-monomethylpyrazolon has no particular anti- 
pyretic action. The presence of the aromatic substituting 
group is, according to Curtius? not essential for the 
physiological action, but Filehne® finds that it is impor- 
tant for the degree of effect. The introduction of the tolyl 
group in place of the phenyl, giving us tolyl-pyrine, does 
not cause any essential change. A compound which is 
better than antipyrine in regard to strength and duration 
of effect-is the 4-dimethyl-amino-antipyrine, which is 
called Pyramidon (IV). 

| IV. PyRAMIDON 





is 
N: C—CH3 
CeHs-N Bee | 
CcCOo— 1 
N(CHs3)2 


1 Michaelis, Ann. Chem., 320, 1 (1902). 
2 Curtius, Ber., 26, 408 (1893). 
3 Filehne, Z. klin. Med., 32, 568 (1907). 


144 3 ORGANIC COMPOUNDS 


[3] Antipyrine (V) is considerably more poisonous than 
the ordinary antipyrine; but when we go to the dimethyl- 
amino derivatives we find the situation reversed. 


V. [3] ANTIPYRINE 
CHs 


CO 
Chip NK flee 
CH == C-CH3 


Iso-antipyrine (VI) is, so far as toxicity is concerned, 
about like ordinary antipyrine.! 





VI. ISo-ANTIPYRINE 





CH; 
N CH 
CeHs-NC T 
fat 
CONGO =O 0g 


The Purine Group } 


This group is important on account of the diuretic 
effect that is found in most of its members. The member 
of the group that was formerly of greatest therapeutic 
importance is caffeine (I). Associated with its diuretic 
action there is a stimulating effect upon the nervous 
system. 


I. CAFFEINE 








H;C—N Wy 

CO C—N-CH3 

Bo Pas 
H3C—N C—N 


1 Kobert, Z. klin. Med., 62, 57 (1907). 


NITROGEN COMPOUNDS 145 


Xanthine (II) has practically no diuretic effect. Of 
its monomethyl derivatives the 3-methyl xanthine (III) 
is more distinctly diuretic, and the 7-methyl-xanthine 
(heteroxanthine) (IV) is only insignificantly diuretic in 
action. 


II. XANTHINE III. 3-MretHyt XANTHINE 














a : ay CO 
| 
C—NH CO C—NH 
rg > me | | P ie 

men — NN H3C—N————-C—N 

IV. Tannese 

= 

CO C—N-CHs 

| | Dex 
HN: C—N 


The dimethyl xanthines are more strongly diuretic than 
caffeine. Of these theobromine (V) is the least active, 
while theophylline (VI) and para-xanthine (VII) act more 
strongly." ; 


V. THEOBROMINE 





HN re : 
CO tow 
H 
| i 
H3C—N: C—N 





Theophylline (Theocine) is the most rapidly powerful 
of all in its action, but its effect diminishes very quickly. 


1 Arch. exp. Path. Pharm., 44, 319 (1900). 


146 ORGANIC COMPOUNDS 


VI. THEOPHYLLINE (THEOCINE) 











H3C-N: rig 
CO C—NH 
S 
| || pew 
H3C-N. C—N 
VII. PARAXANTHINE 
H3C-N ro 
CO C—N oo 
| | pou 
HN C—N 





It has been determined that the effect of theocine is 
due only to the closing of the imide-azol ring! Ethyl- 
methyl-xanthine is similar in action to theobromine.? 
Other members of the group which also act as diuretics 
are ethyl-theobromine, ethyl-para-xanthine and ethyl- 
theophylline. Ethyl-theophylline is weaker than ethyl- 
theobromine.? 

8-dimethyl-amino-para-xanthine (Paraxine) (VIII) acts 
very energetically and persistently but not instantly like 
theophylline. 


VIII. ParaxInE 
H3CN. CO 


| | 
CO C—N—CHs3 

| exon. 
HN: C—N 


1 Dreser, Pfliiger’s Arch., 102, 1 (1904). 
2 Birk, Dissertation, Halle-Wittenburg, 1905. 
* Bergall and Richter, Z. exp. Path., 1, 655 (1905). 








NITROGEN COMPOUNDS 147 


8-dimethyl-amino-heteroxanthine, on the other hand, 
like theophylline, acts intensely but only for a short time.! 

Uric acid (IX) is a diuretic according to Starkenstein,? 
but in large doses it injures the kidneys. 


IX. Uric Acip 





eS 
CO C—NH 
sy 

ee Pas, 
HN C—NH 





3- and 7-methyl uric acid (X), (XI), cause at first anuria, 
then a strong flow of urine. 


X. 3-Metuyt Uric AcIp 











a Ce 
CO cof 
CO 
eek 
H3CN: C—NH 
XI. 7-Mrtuyt Uric Acip 
ah CO 
CO C—N.CH3 
ee ee 
HN: C—NH 





1-3 dimethyl uric acid (XII) has a slight diuretic action 
and isnon-injurious. 1-3-7 trimethyl uric acid (hydroxy- 
caffeine) (XIII) is a strong diuretic and is also non- 
injurious at’ least in the case of rabbits. 


1 Forschback and Weber, Arch. exp. Path. Pharm., 56, 186 


(1907). 
2 Starkenstein, Arch. exp. Path. Pharm., 57, 27 (1907). 


148 : ORGANIC COMPOUNDS 


XII. 1-38 Dimetuyt Uric Acip 











H3C-N CC 
CO Wow 
Bae ee 
H3CN C—NH 
XIII. Hyproxy CAFFEINE 
H3C—WN: a 
CO C—N—CH3 
Sco 
Bae ae 
H3C—N C—NH 





The derivatives of the closely related azinpurine (XIV) 
act as diuretics similarly to the purine derivatives; but 
they are distinguished from the latter in having a stronger 
cramp-excitant effect.! 


XIV. AZINPURINE 





N: re 
am ce 
C—N= 





According to Levene? even thymine (XV) acts like 
the dimethyl and trimethyl xanthines. 





XV. THYMINE 
H ) rae 
a hae 
HN. CH 





1Sachs and Meyerheim, Ber., 41, 3959 (1908). 
2 Levene, Biochem. Zeitschr., 4, 816 (1907). 


NITROGEN COMPOUNDS 149 


Hydrazine, Its Derivatives, and Hydroxylamine 


Hydrazine or diamide, HzN—NHe, is much more 
poisonous than ammonia.! Subcutaneous injection of the 
sulphate in quantities of 0.1 gm. per kg. of body-weight 
causes in the case of a dog, an excitation, then depression 
and finally coma. ‘There occur irregularity of the pulse, 
vomiting, salivation and evacuation of the bowels. The 
quantity of allantoin in the urine, and possibly in the 
saliva is increased. 

The entry of acid radicles into the molecule weakens 
both the chemical reactivity and the physiological ac- 
tivity. Dibenzoyl-diamide has, according to Borissow, a 
weaker action than diamide. Morevoer the action is 
manifested by somewhat different phenomena. The phys- 
iological action is also less in the case of semi-carbazide, 


H2N—CO—NH—N Ha, 
and amino-guanidine, 
H2N—C(NH)—NH—N RH; 
but St soca techiinoro-carhobie acid-hydrazide, 
HO—C,gH4—O—CO—N H—N He 


is said to act about like free hydrazine.” 

The derivatives of phenyl hydrazine were subjected to 
a great deal of investigation, because it was expected that 
among these compounds there might be found substitutes 
for antipyrine. The reason for this expectation was the 
constitutional formula which was originally ascribed to 


1 Loew, Ber., 28, 3203 (1890); Borissow, Z. physiol. Chem., 
19, 499 (1894). 
2 Loew, Chem. Ztg., 22, 349 (1898). 


152 RESUME 


acid, or its ortho-dichlor compound with two molecules of 
2-amino-naphthaline-3-6-disulphonie acid (Trypan red) or 
with other naphthaline 3-6-disulphonic acids. According 
to Ehrlich! other radicles can be introduced into these 
bodies, preferably in the 7 position. Combinations with 
1-8-amino-naphthol-3-6 disulphonic acid are also effective 
against certain trypanosomes.? 

Azoimide is less poisonous for plants than either hydra- 
zine or hydroxylamine. But for mammals it causes 
lightning-like cramps and sometimes immediate death, 
with a dark coloring of the blood. Loew attributes the 
effect to a reaction of the sudden breaking down of the 
protoplasm. 


R&£ésuMk& 


A brief review of our discussion of the organic com- 
pounds may n@w be profitable. We have studied cer- 
tain groupings! which furnish the preliminary basis for 
certain effects. Then we have observed that, given these 
fundamental nuclei, the physiological action of the com- 
pounds may be varied—either weakened or strengthened 
or modified by the action of individual side chains. 
Among those side chains which seem to release the latent 
action of the nucleus we find those groups which also 
favor an increased chemical activity. The strikingly 
noticeable groups of this sort are the amino, hydroxyl 
and carbonyl groups. In fact these groups are so power- 
ful in this manner that it is frequently necessary to intro- 
duce other groups with a weakening effect before the 
compound is suitable for safe and reliable therapeutic 


1 Ehrlich, Berl. klin. Wochschr., 44, No. 9-12 (1907). 
2 Nicolle and Mesnil, Ann. inst. Pasteur, 20, 417, 513 (1906). 
3 Loew, Ber., 24, 2947 (1891). 


RESUME 153 


use. Such a weakening of action may naturally be pro- 
duced upon amino bodies by introducing acid constituents. 
A possibility which is to be guarded against is the carrying 
of this weakening effect so far as to destroy the action 
entirely. Such is often the case with carboxylic acids 
and even more frequently with sulphonic acids. This is 
easily understood from a chemical standpoint, because 
we have strongly acid groups introduced into basic com- 
pounds and we should expect this to wholly change the 
character of the compound. But this same phenomenon 
is also observed in the case of compounds which are 
already of an acid nature such as phenols. In such cases 
we should expect an increase rather than a decrease of 
effect upon introducing an acid radicle. We are, however, 
reasonably certain in saying that in this case there is 
another factor which plays a very large part. This 
factor is the distribution coefficient. The carboxylic 
acids and sulphonic acids must of course enter the body 
fluids in the form of their alkali salts, and these substances 
are not nearly so easily taken up by the tissue cells as are 
the free phenols. 

The alkyls we found to play an important réle in several 
ways. In the first place, we repeatedly observed that 
their accumulation about certain groups is a condition 
for sleep-producing effects. The alkyl groups also have 
a specific action when combined to the ring by means of 
oxygen, thus acting as closures for hydroxyl or carboxyl 
groups. In the case of hydroxyl groups their function is 
frequently a softening of the otherwise violent reaction. 
In the case of carboxyl groups their effect is generally in 
the nature of a neutralization of the disturbing effect of 
violent action. The alkoxyl group occasionally also 
strengthens an effect; but such action is probably explica- 
ble in most cases by a change in the distribution coefficient. 


154 RESUME 


Although in general the alkyl groups are about the same 
in effect, -yet in some cases there are decided differences. 
This is particularly noticeable in the case of the sleep- 
producing compounds. In fact in this respect special 
action was for some time assigned to the ethyl group. 
But more recent observations have shown that the propyl 
groups are at least the equal if not superior to the ethyl. 
This seems to be the case with some series where equi- 
valence of all alkyl radicles was assumed merely from an 
observation and comparison of the methyl and _ ethyl 
compounds. Thus, according to Stiirmer and Liiders ! the 
propyl ester of para-amino benzoic acid (Propeesin) is 
essentially more active than the corresponding ethyl 
ester (Anzesthesin). 

An a priori opinion, that is only too readily conceived, 
is that the combination of several substances which act 
in a similar direction will result in an especially desirable 
action. But this has often led to disillusionment and 
failure. Examples of such failures we noted in the com- 
binations of salicylic acid with other febrifuges. More 
recently Stiirmer and Liiders? report a fact which 
appeared, to them at least, to be very striking—namely 
that the esters of para-amino benzoic acid with phenols 
and hydroaromatic alcohols (as guaiacol, thymol, men- 
thol), which in themselves have an anesthetic action, are 
really weaker in effect than the corresponding com- 
pounds of aliphatic alcohols. There may be several 
reasons for this. In the first place it is likely that 
such compounds can act only in the form of their 
decomposition products. This splitting up proceeds 
only with difficulty, as is generally the case for these sali- 
cylic acid compounds. Then, too, it may be that in 


1 Stiirmer and Liiders, Deut. med. Wochschr., 34, 2314 (1908). 
2 Ibid. 


RESUME 155 


order to be effective, both components must find anchor- 
age at the same point. If such were the case it is quite 
possible that the physiologically less active component 
may hold off or stand in the way of the more active one. 
Even in cases where the effects of the components do 
seem to be additive in a positive manner, there still 
remains to be decided by experimentation in each individ- 
ual case, whether the proportion of the two which holds in 
a chemical combination is that proportion which gives 
the best physiological results. ‘Therefore we must con- 
fess that work which looks toward a synthesis of such 
compounds is in general not a promising field. . 

It will of course be understood that this treatise has 
not attempted to refer to all the observations which 
are relevant to the subject. Only the most important 
and most thoroughly investigated groups have been 
considered. We have not touched upon the interesting 
subject of the effect of constitution upon the odor and 
taste of chemical compounds. Those who are inter- 
ested in this subject we would refer to the writings of 
Zwaardemaker, ‘‘Die Physiologie des Geruchs,” trans- 
lated by Junker von Landegg. 

Unfortunately, experimentation in this field must 
suffer, among other things, from the considerable influence 
of the subjectivity of the observer. For example, opin- 
ions are wholly contradictory whether p-anisol-carbamide 
has a sweet taste like the corresponding phenetol deriva- 
tive or not. We must also remind our readers of the 
complete work of Frankel, “Die Artzneimittelsynthese 
auf Grundlage der Beziehungen zwischen Chemischem 
Aufbau und Wirkung, 2. Aufl., Berlin, 1906, a work which 
has served largely as a guide for the older literature. 





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written and enlarged. 39 colored plates. 367 illustra- 


tions. 8vo. cloth. 369 pp. net, $6.00 

BECHHOLD, H. Colloids in Biology and Medicine. 

Translated by J. G. Bullowa, M.D. In Press. 
BEEKMAN, J. M. Principles of Chemicai Calculations. 

In Press. 

BENNETT, HUGH G. . The Manufacture of Leather. 

Ito illustrations. 8vo. cloth. 438 pp. net, $4.50 


BERNTHSEN, A. A Text-book of Organic Chemistry. 
English translation. Edited and revised by J. J. Sud- 
borough. Illus. 1t2mo. cloth. 690 pp. net, $2.50. 

BERSCH, J. Manufacture of Mineral Lake Pigments. 
Translated by A. C. Wright. 43 illustrations. 8vo. 
cloth. 476 pp. net, $5.00 

BEVERIDGE, JAMES. Papermaker’s Pocketbook. Spe- 
cially compiled for .paper mill operatives, engineers, 
chemists and office officials. Second and Enlarged 
Edition. Illus. t2mo. cloth. 211 pp. net, $4.00 

BIRCHMORE, W.H. The Interpretation of Gas Analyses. 
Illustrated. 12mo. cloth. 75. pp. net, $1.25 

BLASDALE, W. C. Principles of Quantitative Analysis. 
An introductory course. 7o illus. 51%4x7'%. cloth. 
404 pp. net, $2.50 

BLUCHER, H. Modern Industrial Chemistry. Trans- 
lated by J. P. Millington. Illus. 8vo. cloth. 795 
pp- net, $7.50 

BLYTH, A. W. Foods: Their Composition and Analysis. 
A manual for the use of analytical chemists, with an 
introductory essay on the History of Adulterations. 
Sixth Edition, thoroughly revised, enlarged and re- 
written. Illustrated. 8vo. cloth. 634 pp. $7.50 

Poisons: Their Effects and Detection. A manual for 

the use of analytical chemists and experts, with an 





LIST OF CHEMICAL BOOKS 3 





—_ 


introductory essay on the Growth of Modern Toxicol- 
ogy. Fourth Edition, revised, enlarged and rewritten. 
Illustrated. 8vo. cloth. 772 pp. $7.50 
BOCKMANN, F. Celluloid; Its Raw Material, Manufac- 
ture, Properties and Uses. 49 illustrations. 12mo. cloth. 


120 pp. net, $2.50 
BOOTH, WILLIAM H. Water Softening and Treatment. 
gi illustrations. 8vo. cloth. 310 pp. net, $2.50 


BOURCART, E. Insecticides, Fungicides, and Weed 
Killers. Translated by D. Grant. 8vo. cloth. 500 pp. 
net, $4.50 

BOURRY, EMILE. A Treatise on Ceramic Industries. 
A complete manual for pottery, tile, and brick manu- 
facturers. A revised translation from the French by 
Alfred B. Searle. 308 illustrations. 12 mo. cloth. 
488 pp. net, $5.00 
BRISLEE, F. J. An Introduction to the Study of Fuel. 
A text-book for those entering the engineering, chem- 
ical and technical industries. 60 ill. 8vo. cloth. 293 
pp. (Outlines of Industrial Chemistry.) net, $3.00 
BROWN, HAROLD. Rubber, Its Sources, Cultivation and 
Preparation. Ill. 6x 834. 237 pp. $2.00 
BRUCE, EDWIN M. Detection of the Common Food 
Adulterants. Illus. 1t2mo. cloth. gopp. net, $1.25 
BUSKETT, E. W. Fire Assaying. A practical treatise on 
the fire assaying of gold, silver and lead, including 
descriptions of the appliances used.. Illustrated. 12mo. 


cloth. 112 pp. net, $1.25 
BYERS, HORACE G., and KNIGHT, HENRY G. Notes 
on Qualitative Analysis. Second Edition, revised. 
8vo. cloth. 192 pp. net, $1.50 


CAVEN, R. M., and LANDER, G. D. Systematic Inor- 
ganic Chemistry from the Standpoint of the Periodic 


4 D. VAN NOSTRAND COMPANY’S 





Law. <A text-book for advanced students. Illustrated. 
12mo. cloth. 390 pp. net, $2.00 
CHRISTIE, W. W. Boiler-waters, Scale, Corrosion, Foam- 
ing. 77 illustrations. 8vo. cloth. 242 pp. net, $3.00 
Water, Its Purification and Use in the Industries. 
79 illus., 3 folding plates, 2 colored inserts. 12mo. 
cloth. 230 pp.. net, $2.00 
CHURCH’S Laboratory Guide. A manual of practical 
_ chemistry for colleges and schools, specially arranged 
for agricultural students, Ninth Edition, revised and 
partly rewritten by Edward Kinch. Illustrated. 8vo. 
cloth, 365 pp. net, $2.50 
CORNWALL, H. B. Manual of Blow-pipe Analysis. 
Qualitative and quantitative. With a complete system 
of determinative mineralogy. Sixth Edition, revised. 
70 illustrations. 8vo. cloth. 310 pp. net, $2.50 
CROSS, C. F., BEVAN, E. J., and SINDALL, R. W. 
Wood Pulp and Its Uses. With the collaboration of 
W. N. Bacon. 30 illustrations. 12mo. cloth. 281 
pp. (Van Nostrand’s Westminster Series.) net, $2.00 
a@’ALBE, E. E. F. Contemporary Chemistry. A survey 
of the present state, methods, and tendencies of chemi- 
cal science. 1I2mo. cloth. 172 pp. net, $1.25 
DANBY, ARTHUR. Natural Rock Asphalts and Bitu- 
mens. Their Geology, History, Properties and Indus- 
trial Application, Illustrated. 12mo. cloth. 254 pp. 





net, $2.50 
DEERR, N. Cane Sugar. 280 illustrations. 61% x93. 
cloth. 608 pp. net, $7.00 


DUMESNY, P., and NOYER, J. Wood Products, Dis- 
tillates and Extracts. Translated by D. Grant. 103 
illustrations. 8vo. cloth. 320 pp. net, $4.50 

DUNSTAN, A. E., and THOLE, F. B. A Text-book of 
Practical Chemistry for Technical Institutes. 52 illus- 
trations. I2mo. cloth. 345 pp. net, $1.40 


LIST OF CHEMICAL BOOKS 5 

DYSON, S. S., and CLARKSON, S. S. Chemical Works, 
Their Design, Erection, and Equipment. §8o illustra- 
tions, 9 folding plates. 8vo. cloth. 220pp. net, $7.50 
ELIOT, C. W., and STORER, F. H. A Compendious Man- 
ual of Qualitative Chemical Analysis. Revised with 
the co-operation of the authors, by William R. 
Nichols. Twenty-second Edition, newly revised by 
W.B. Lindsay. Ill. 12mo, cloth. 205 pp. net, $1.25 
ELLIS, C. Hydrogenation of Oils, Catalysis and Catalyzers, 
and the Generation of Hydrogen. Second Edition, re- 
vised and enlarged. In Press 
ENNIS, WILLIAM D. Linseed Oil and Other Seed Oils. 
An industrial manual. 88 illustrations. 8vo. cloth. 
336 pp. net, $4.00 
ERMEN, W.F. A. The Materials Used in Sizing. ‘Their 
chemical and physical properties, and simple methods 
for their technical analysis and valuation. Illustrated. 
12mo. cloth. 130 pp. net, $2.00 
FAY, IRVING W. The Chemistry of the Coal-tar Dyes. 
8vo. cloth. 473 pp. net, $4.00 
FERNBACH, R. L. Chemical Aspects of Silk Manu- 
facture. 12mo. cloth. 84 pp. net, $1.00 
Glue and Gelatine. A practical treatise on the 
methods of testing and use. Illustrated. 8vo. cloth. 








208 pp. net, $3.00 
FIRTH, J: B. Practical Physical Chemistry. Ill. 5.x 7. 
cloth. 189 pp. net, $1.00 


FISCHER, E. Introduction to the Preparation of Or- 
ganic Compounds. Translated from the new (eighth) 
German edition by R. V. Stanford. Illustrated. 
r2mo. cloth. 194 pp. net, $1.25 

FOYE, J.C. Chemical Problems. Fourth Edition, revised — 
and enlarged. 16mo. cloth. 145 pp. (Van Nos- 
trand- Science Series, No. 69.) $0.50 

FRANZEN, H. Exercises in Gas Analysis. Translated 





6 D. VAN NOSTRAND COMPANY'S 


from the first German edition, with corrections and 
additions by the author, by Thomas Callan. 30 dia- 
grams. 5x71!4. cloth. 127 pp. net, $1.00 


FRITSCH, J. The Manufacture of Chemical Manures. 
Translated from the French, with numerous notes, by 
Donald Grant. 69 illus., 108 tables. 8vo. cloth. 


355 pp. net, $4.00 
GROSSMANN, J. Ammonia and Its Compounds. [IIlus- 
trated. 12mo. cloth. 151 pp. net, $1.25 


HALE, WILLIAM J. Calculations in General Chemistry. 
- With definitions, explanations and problems. —Fi/th 
Edition, revised. 12mo. cloth. 185 pp. _ net, $1.00 
HALL, CLARE H. Chemistry of Paints and Paint Ve- 


_hicles. 8vo. cloth. 141 pp. net, $2.00 
HILDITCH, T. P. A Concise History of Chemistry. 
16 diagrams. I2mo. cloth. 273 pp. net, $1.25 


HOPKINS, N. M. Experimental Electrochemistry : Theo- 
retically and Practically Treated. New Edition. 


3 In Press. 
HOULLEVIGUE, L. The Evolution of the Sciences. 
8vo. cloth. 377 pp. net, $2.00 


HUBNER, JULIUS. Bleaching and Dyeing ef Vegetable 
Fibrous Materials. 95 illus. (many in two colors). 
8vo. cloth. 457 pp. net, $5.00 


HUDSON, 0. F. Iron and Steel. An introductory text- 
book for engineers and metallurgists. With a section 
on Corrosion by Guy D. Bengough. 47 illus: 8vo. 
cloth. 184 pp. net, $2.00 

HURST, GEO. H. Lubricating Oils, Fats and Greases. 
Their origin, preparation, properties, uses, and analy- 
sis. Third Edition, revised and enlarged, by Henry 
Leask. 74 illus. 8vo. cloth. 405 p. net, $4.00 

HURST, G. H., and SIMMONS, W. H. Textile Soaps and 


LISE (OF ; CHEMICAL: BOOKS 2 





Oils. Second Edition, revised and partly rewritten. 

11 illustrations. 514x834. 204 pp. net, $3.00 
HYDE, FREDERIC §. Solvents, Oils, Gums, Waxes and 

Allied Substances. 514 x8%%. cloth. 182 pp. 


net, $2.00 
INGLE, HERBERT. Manual of Agricultural Chemistry. 
Illustrated. 8vo. cloth. 388 pp. net, $3.00 


JOHNSTON, J. F. W. Elements of Agricultural Chem- 
istry. Revised and 1ewritten by Charles A. Cameron 
and C. M. Aikman. Nineteenth Ediiton. Illustrated. 
12mo. cloth. 502 pp. $2.60 

JONES, HARRY C. A New Era in Chemistry. Some of 
the more important developments in general chemis- 
try during the last quarter of a century. Illustrated. 
12mo. cloth. 336 pp. net, $2.00 

KEMBLE, W. F., and UNDERHILL, C. R. The Periodic 
Law and the Hydrogen Spectrum. Illustrated. 8vo. 
paper. 16 pp. oy net, $0.50 

KERSHAW, J. B.C. Fuel, Water, and Gas Analysis, for 
Steam Users. 50 ill. 8vo. cloth. 178 pp. net, $2.50 

Electro-Thermal Methods of Iron and Steel Produc- 

tion. With an introduction by Dr. J. A. Fleming, 

F.R.S. 50 tables, 92 illustrations. 5142x8%. cloth. 





262 pp. net, $3.00 
KNOX, JOSEPH. Physico-chemical Calculations. 12mo. 
cloth. 196 pp. aa net, $1.00 © 


—— The Fixation of Atmospheric Nitrogen. Illustrated. 
5x7%. cloth. 120 pp. (Van Nostrand’s Chemical 
Monographs. ) net, $0.75 

KOLLER, T. Cosmetics. A handbook of the manufac- - 
ture, employment and testing of all cosmetic materials 
and cosmetic specialties. Translated from the German 
by Charles Salter. 8vo. cloth. 262 pp. net, $2.50 

—— Utilization of Waste Products. A treatise on the 


8 D. VAN NOSTRAND COMPANY’S 





rational utilization, recovery and treatment of waste 
products of all kinds. Second Revised and Enlarged 
Edition. 22 illustrations. 534 x 834. cloth. 336 pp. 
net, $3.00 

KOPPE, S. W. Glycerine. Its introduction, uses and 
examination. For chemists, perfumers, soapmakers, 
pharmacists, and explosives technologists. 7 illustra- 


tions. 544x7Y%. 260 pp. $2.50 


KREMANN, R. The Application of Physico-chemical 
Theory to Technical Processes and Manufacturing 
Methods. Authorized translation by Harold E. Potts, 
M.Sc. 35 diagrams. 8vo. cloth. 215 pp. net, $2.50 


KRETSCHMAR, KARL. Yarn and Warp Sizing in All 
Its Branches. ‘Translated from the German by C. 
Salter. 122 illus. 8vo. cloth. 192 pp. net, $4.00 


LAMBORN, L. L. Modern Soaps, Candles and Glycerin. 
224 illustrations. 8vo. cloth. 700 pp. net, $7.50 
Cotton Seed Products. 79 illus. 8vo. cloth. 253 pp. 
, net, $3.00 

LASSAR-COHN. Introduction to Modern Scientific 
Chemistry. In the form of popular lectures suited for 
University Extension students and general readers. 
Translated from the Second German Edition by M. M. 
Pattison Muir. Illus. t2mo. cloth. 356 pp. $2.00 


LETTS, E. A. Some Fundamental Problems in Chemis- 
try: Old and New. 44 illustrations. 8vo. cloth. 236 
pp. net, $2.00 

LLOYD, STRAUSS L. Fertilizer Materials. In Press 


LUNGE, GEORGE. Technical Methods of Chemical 
Analysis. Translated from the Second German Edition 
by Charles A. Keane, with the collaboration of eminent 
experts. Complete in three volumes. Six parts. 448 
illustrations. 614x9'%4. cloth. 3494 pp. net, $48.00 





LIST OF CHEMICAL BOOKS 9g 





Vol. I. (in two parts). 201 illustrations. 61 x9%. 


cloth. 1024 pp. net, $15.00 
Vol. II. (in two parts). 149 illustrations. 642 x9”. 
cloth. 1294 pp. net, $18.00 
Vol. III. (in two parts). 98 illustrations. 61% x9”. 
cloth. 1174 pp. net, $18.00 


Technical Chemists’ Handbook. ‘Tables and meth- 
ods of analysis for manufacturers of inorganic chemi- 
cal products. Illus. r2mo, leather. 276 pp. net, $3.50 
Coal, Tar and Ammonia. Fifth and Enlarged Edi- 
tion. In-three volumes, not sold separately. Ill. 6x09. 
cloth. 1600 pp. net, $18.00 
The Manufacture of Sulphuric Acid and Alkali. 
A theoretical and practical treatise. 
Vol. I.. Sulphuric Acid. Fourth Edition, Sidi Bed 
In three parts, not sold separately. 543 illustrations. 
8vo. cloth. 1665 pp. net, $18.00 
Vol. II. Sulphate of Soda, Hydrochloric Acid, Leblanc 
Soda. Third Edition, much enlarged. In two parts, 
not sold separately. 335 illustrations. 8vo. cloth. 
1044 pp. : net, $15.00 
Vol. III. Ammonia Soda. Various Processes of AlI- 
kali-making, and the Chlorine Industry. 181 illus- 
trations. 8vo. cloth. 784 pp. = net, $10.00 
Vol. IV. Electrolytical Methods. In Press. 
Technical Gas Analysis. 143 illustrations. 6x9. 
cloth. 422 pp. | net, $4.00 
McINTOSH, JOHN G. The Technology of Sugar. Third 
Edition, revised and enlarged. 244 illustrations. 
6x 834. 540 pp. $5.00 
McINTOSH, JOHN G. The Manufacture of Varnish and 
Kindred Industries. I[llus.. 8vo. cloth. In 3 volumes. 
Vol. I. Oil Crushing, Refining and Boiling; Manu- 
facture of Linoleum; Printing and Lithographic Inks; 














40 D. VAN NOSTRAND COMPANY’S 





India Rubber Substitutes. 29 illus. 160 pp. net, $3.50 
Vol. II. Varnish Materials and Oil Varnish Making. 


66 illus. 216 pp. net, $4.00 
Vol. Ill. Spirit Varnishes and Varnish Materials. 
64 illus. 492 pp. ae net, $4.50 


MARTIN, G. Triumphs and Wonders of Modern Chem- 
istry. A popular treatise on modern chemistry and 
its marvels written in non-technical language. 76 il- 
lustrations. 12mo. cloth. 358 pp. net, $2.00 

MARTIN, GEOFFREY. Modern Chemistry and Its 
Wonders. A popular account of some of the more re- 
markable recent advances in chemical science. 65 il- 


lustrations. 514x734. 267 pp. $2.00 
_MELICK, CHARLES W. Dairy Laboratory Guide. 52 
illustrations. 12mo. cloth. 135 pp. net, $1.2% 


MERCK, E. Chemical Reagents: Their Purity and Tests. 
Second Edition, revised. 6xg. cloth. 210 pp. $1.00 
MIERZINSKI, $. The Waterproofing of Fabrics. Trans- 
lated from the German by A. Morris and H. Robson. 
Second Edition, revised and enlarged. 29 illustrations. 


5x7%. 140 pp. net, $2.50 
MITCHELL, C. A. Mineral and Aerated Waters. 111 
illustrations. 8vo. cloth. 244 pp. net, $3.00 


MITCHELL, C. A., and PRIDEAUX, R. M. Fibres Used 
in Textile and Allied Industries. 66 illustrations. 
8vo. cloth. 208 pp. net, $3.00 

MUNBY, A. E. _ Introduction to the Chemistry and 
Physics of Building Materials. Illus. 8vo. cloth. 365 
pp. (Van Nostrand’s Westminster Series.) net, $2.00 

MURRAY, J. A. Soils and Manures. 33 illustrations. 
8vo. cloth. 367 pp. (Van Nostrand’s Westminster 
Series. } net, $2.00 

NAQUET, A. Legal Chemistry. A guide to the detec- 
tion of poisons as applied to chemical jurisprudence. 


LIST OF CHEMICAL BOOKS 11 





Translated, with additions, from the French, by. J. P. 
Battershall. Second Edition, revised with additions. 
t2mo. cloth. 190 pp. $2.00 
NEAVE, G. B., and HEILBRON, I. M. The Identifica- 
tion of Organic Compounds. 12mo, cloth. 111 pp. 
net, $1.25 
NORTH, H. B. Laboratory Experiments in General 
Chemistry. Second Edition, revised. 36 illustrations. 
5144.x 73%. cloth. 212 pp. net, $1.00 
OLSEN, J. C.: A Textbook of Quantitative Chemical 
Analysis by Gravimetric and Gasometric Methods. 
Including 74 laboratory exercises giving the analysis 
of pure salts, alloys, minerals and technical products. 
Fifth Edition, revised and enlarged. ~ In Press 
PAKES, W. C. G., and NANKIVELL, A. T. The Science 
of Hygiene. A text-book of laboratory practice. 80 
illustrations. 1I2mo. cloth. 175 pp. net, $1.75 


PARRY, ERNEST J. The Chemistry of Essential Oils 
and Artificial Perfumes. Second Edition, thoroughly 
revised ond greatly enlarged. Illustrated. 8vo. cloth. 
554 pp. net, $5.00 

— Food and Drugs. In2volumes. Illus. 8vo. cloth. 
Vol. I. The Analysis of Food and Drugs (Chemical 
and Microscopical). 59 illus. 724 pp. net, $7.50 
Vol. II]. The Sale of Food and Drugs Acts, 1873- 
1907. 184 pp. net, $3.00 | 

PARTINGTON, JAMES R. A Text-book of Thermo- 
dynamics (with special reference to Chemistry). 91 


diagrams. 8vo. cloth. 550 pp. net, $4.00 
-— Higher Mathematics for Chemical Students. 44 
diagrams. 12mo.. cloth. 272 pp. net, $2.00 


PERKIN, F. M. Practical Methods of Inorganic Chem- 
istry. Illustrated. 12mo. cloth. 152 pp. net, $1.00 


12 D. VAN NOSTRAND COMPANY’S 





PERKIN, F. M., and JAGGERS, E. M. Textbook of Ele- 
mentary Chemistry. 77 illustrations. 434 x7. cloth. 
342 pp. net, $1.00 


PLATTNER’S Manual of Qualitative aud Quantitative 
Analysis with the Blowpipe. Eighth Edition, revised. 
Translated by Henry B. Cornwall, assisted by John 
H.: Caswell, from the Sixth German Edition, by Fried- 
rich Kolbeck. 87 ill. 8vo. cloth. 463 pp. net, $4.00 

POLLEYN, F. Dressings and Finishings for Textile 
Fabrics and Their Application. Translated from ihe 
Third German Edition by Chas, Salter. 60 illustra- 
tions. 8vo. cloth. 279 pp. net, $3.00 

POPE, F. G. Modern Research in Organic Chemistry. 
261 diagrams. 12mo. cloth. 336 pp. net, $2.25 


PORRITT, B. D. The Chemistry of Rubber. 5x71. 
cloth. 100 pp. (Van Nostrand’s Chemical Mono- 


graphs. ) net, $0.75 
POTTS, HAROLD E. Chemistry of the Rubber Industry. 
— 8vo. cloth. 163 pp. net, $2.00 


PRESCOTT, A. B. Organic Analysis. A manual of the 
descriptive and analytical chemistry of certain carbon 
compounds in common use. Sixth Edition. Illus- 
trated. 8vo. cloth. 533 pp. ; $5.00 

PRESCOTT, A. B., and JOHNSON, 0. C. . Qualitative 
Chemical Analysis. Eighth Edition, revised and en- 
larged. In Press 

PRESCOTT, A. B., and SULLIVAN, E. C. First Book in 
Qualitative Chemistry.. For studies of water solution 
and mass action. Eleventh Edition, entirely rewritten. 
12mo. cloth. I50 pp... net, $1.50 

PRIDEAUX, E. B. R. Problems in Physical Chemistry 
with Practical Applications. 13 diagrams. 8vo. cloth. 
323 pp. net, $2.00 


A 


LIST OF CHEMICAL BOOKS 13 
PROST, E. Manual of Chemical Analysis. As applied 
to the assay of fuels, ores, metals, alloys, salts, and 
other mineral products. Translated from the original 
by J. C. Smith. Illus. 8vo. cloth. 300 pp. net, $4.50 


PYNCHON, T. R. Introduction to Chemical Physics. 
Third Edition, revised and enlarged. 269 illustrations. 
8vo. cloth. 575 pp. $3.00 

RICHARDS, W. A., and NORTH, H. B. A Manual of 
Cement Testing. [or the use of engineers and chem- 
ists in colleges and in the field. 56 illustrations. 
12mo. cloth. 147 pp. net, $1.50 

RIDEAL, S. Glue and Glue Testing. Second Edition, 
revised and enlarged. 14 illustrations. 534 x 834. 
cloth. 194 pp. net, $4.00 

ROGERS, ALLEN. A Laboratory Guide of Industrial 
Chemistry. Illustrated. 8vo. cloth. 170 pp. net, $1.50 


ROGERS, ALLEN (Editor). Industrial Chemistry. A 
manual for the student and manufacturer. Second 
Edition, thoroughly revised and enlarged. Written 
by a staff of eminent specialists. 304 illustrations. 


614% x 934: cloth. 1026 pp. net, $5.00 
ROGERS, ALLEN. Elements of Industrial Chemistry. 


An abridgement of The Manual of Industrial Chem- 
istry. | In Press 
ROHLAND, PAUL. The Colloidal and Crystalloidal State 
of Matter. Translated by W..J. Britland and H. E. 
Potts. ramo. cloth. 54 pp. net, $1.25 
ROTH, W. A. Exercises in Physical Chemistry. Author- 
ized translation by A. T. Cameron. 4g illustrations. 
8vo. cloth. 208 pp. net, $2.00 
SCHERER, R. Casein: Its Preparation and Technical 
Utilization. Translated from the German by Charles 
Salter. Second Edition, revised and enlarged. Il- 
lustrated. 8vo. cloth. 1096 pp. net, $3.00 





14 D. VAN NOSTRAND es aN e's 





ome Seaver heed 3s bigs cena 


SCHIDROWITZ, P. Rubber. Its Production and Indus- 
trial Uses. Plates, 83 illus. 8vo. cloth. 320 pp. 

net, $5.00 

SCHWEIZER, V. Distillation of Resins, Resinate Lakes 

and Pigments. Illustrated. 8vo, cloth. 183 pp. net, $3.50 

SCOTT, W. W. Qualitative Chemical Analysis. A labo- 

ratory manual. Second Edition, thoroughly revised. 


Illus. 8vo... cloth. 180 pp. net, $1.50 
SCOTT, W. W. (Editor). Technical Methods of Analysis. 
Ill. 6x9. 600 pp. In Press 


SCUDDER, HEYWARD. Electrical Conductivity and 
Ionization Constants of Organic Compounds. 6x09. 





cloth. 575 pp. net, $3.00 
SEARLE, ALFRED B. Modern Brickmaking. 260 illus- 
trations. 8vo. cloth. 449 pp. net, $5.00 
Cement, Concrete and Bricks. 113 illustrations. 
54x84. cloth. 415 pp. net, $3.00 


SEIDELL, A. Solubilities of Inorganic and Organic Sub- 
stances. A handbook of the most reliable quantitative 
solubility determinations. Second Printing, corrected. 
8vo. cloth. 367 pp. i net, $3.00 

SENTER, G. Outlines of Physical Chemistry. Second 
Edition, revised. Illus. 12mo. cloth. 4o1 pp. $1.75 

A Text-book of Inorganic Chemistry. 90 illustra- 
tions, 1I2mo. cloth. 595 pp. net, $1.75 

SEXTON, A. H. Fuel and Refractory Materials. Second 
Ed., revised. 104 illus.. 12mo. cloth. 374 pp. net, $2.00 

Chemistry of the Materials of Engineering. Illus. 
12mo. cloth. 344 pp. net, $2.50 

SIMMONS, W. H., and MITCHELL, C. A. Edible Fats 
and Qils. Their composition, manufacture and analy- 
sis. Illustrated. 8vo. cloth. 164 pp. net, $3.00 

SINDALL, R. W. The Manufacture of Paper. 58 illus. 
8vo. cloth. 285 pp . (Van Nostrand’s Westminster 
Series. ) | net, $2.00 








LIST OF CHEMICAL BOOKS 15 


<mitel 





SINDALL, R. W., and BACON, W. N. The Testing of 
Wood Pulp. A practical handbook for the pulp and 
paper trades. Illus. 8vo. cloth. 150 pp. net, $2.50 

SMITH, J. C. The Manufacture of Paint. A manual for 
paint manufacturers, merchants and painters. Second 
Edition, revised and enlarged. §8o illustrations. 51% x 
834. cloth. 286 pp. net, $3.50 

SMITH, W. The Chemistry of Hat Manufacturing. 
Revised and edited by Albert Shonk. Illustrated. 
12mo. cloth. 132 pp. net, $3.00 

SOUTHCOMBE, J. E. Chemistry of the Oil Industries. 
Illus. 8vo. cloth. 209 pp. net, $3.00 

SPEYERS, ©. L. Text-book of Physical Chemistry. 20 
illustrations. 8vo. cloth. 230 pp. net, $2.25 

SPIEGEL, L. Chemical Constitution and Physiological 
Action. Translated by C. Luedeking and A. C. 


Boylston. 5x7%. cloth. 160 pp. net, $1.25 
STEVENS, H. P. Paper Mill Chemist. 67 illustrations. 
82 tables. 16mo. cloth. 280 pp. net, $2.50 


SUDBOROUGH, J. J., and JAMES, J. C. Practical Or- 
ganic Chemistry. 92 illustrations. I2mo. cloth. 
394 pp. net, $2.00 

TERRY, H. L. India Rubber and Its Manufacture. 
18 illustrations. 8vo. cloth. 303 pp. (Van Nos- 
trand’s Westminster Series.) net, $2:00 

TITHERLEY, A. W. Laboratory Course of Organic | 
Chemistry, Including Qualitative Organic Analysis. 
Illustrated. 8vo. cloth. 235 pp. net, $2.00 

TOCH, M. Chemistry and Technology of Paints. Second 
Edition, revised and enlarged. Ill. 6x9. 373 pp. 

net, $4.00 

TOCH, M. Materials for Permanent Painting. A manual 
for manufacturers, art dealers, artists, and collectors. 
With full-page plates. Illustrated. 12mo. cloth. 
208 pp. net, $2.00 


sb D. VAN NOSTRAND COMPANY’S 





TUCKER, J. H. A Manual of Sugar Analysis. Sixth 
Edition. 43 illustrations. 8vo. cloth. 353 pp. $3.50 


UNDERWOOD, N., and SULLIVAN, T. V.. Chemistry and 
Technology of Printing Inks. 9 illustrations. 6x9. 
cloth. 145 pp. net, $3.00 


VAN NOSTRAND’S Chemical Annual. Edited by John 
C. Olsen and Alfred Melhado. A handbook of useful 
data for analytical manufacturing and investigating 
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